USP15 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 15
HGNC Gene Symbol
USP15
Identifiers
hgnc:12613 NCBIGene:9958 uniprot:Q9Y4E8
Orthologs
mgi:101857 rgd:628795
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP15
Number of Papers
167 retrieved on 2023-02-19

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score greater than 90 is considered significantly similar.

DepMap Correlations

Symbol Name DepMap Correlation Evidence CCLE Correlation CCLE Z-score CCLE p-value (adj) CCLE Significant CMAP Score CMAP Type
PLAA phospholipase A2 activating protein 0.227 0.28 1.47 2.33e-07
SAV1 salvador family WW domain containing protein 1 0.226 Reactome (1) -0.14 -0.87 2.18e-02
USP14 ubiquitin specific peptidase 14 0.218 BioGRID INDRA (1) Reactome (4) 0.41 2.17 3.99e-15
UBE2R2 ubiquitin conjugating enzyme E2 R2 0.217 Reactome (2) 0.41 2.18 2.60e-15
CAND1 cullin associated and neddylation dissociated 1 0.217 INDRA (1) Reactome (2) 0.37 1.94 3.50e-12
UBA6 ubiquitin like modifier activating enzyme 6 0.213 Reactome (2) 0.55 2.92 1.99e-28
NF2 NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor 0.207 Reactome (1) -0.05 -0.36 4.74e-01

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP15using the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier GO Name GO Type p-value p-value (adj.) q-value
GO:0035329 hippo signaling Biological Process 8.15e-05 2.22e-02 1.06e-02

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out USP15 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
RPS24 ribosomal protein S24 7.41e-01 1.87e-13 4.13e-09
NPM1 nucleophosmin 1 2.82e-01 6.25e-07 6.90e-03

Gene Set Enrichment Analysis

There were too few differentially expressed genes to run a meaningful GSEA.

Literature Mining

INDRA was used to automatically assemble known mechanisms related to USP15 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

psp cbn pc bel_lc signor biogrid tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi minerva creeds ubibrowser acsn | geneways tees gnbr semrep isi trips rlimsp medscan eidos sparser reach
USP15 deubiquitinates TRIM25. 10 / 13
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The sfRNA of an epidemic DENV strain bound to TRIM25 in a sequence specific manner, and this interaction prevented TRIM25 deubiquitination and stabilization by USP15, thereby blunting the RIG-I-mediated IFN response [XREF_BIBR].
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USP15 was originally identified as a DUB enzyme that interacts with TRIM25, serving to cleave the K48-ubiquitin chain that maintains TRIM25 in an inactive state; thus, de-ubiquitination of TRIM25 by USP15 potentiates TRIM25 dependent activation of RIG-I [XREF_BIBR].
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We found that upon binding to TRIM25, USP15 deubiquitylated TRIM25, which stabilized the protein and thereby led to a sustained RIG-I-dependent antiviral response (XREF_FIG).
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Furthermore, wild-type USP15, but not its catalytically inactive C783A mutant, decreased the polyubiquitylation of TRIM25 that was caused by ectopically expressed HOIL-1L and HOIP (XREF_FIG).
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We next addressed whether USP15 deubiquitylated endogenous TRIM25 in the context of viral infection.
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The protein levels of TRIM25 may also have to be at a certain level in order for it to productively ubiquitinate RIG-I, as the ubiquitin protease USP15 deubiquitinates TRIM25 at later time points in viral infection (109).
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For instance, USP15 interacts with and deubiquitinates TRIM25 when it is ubiquitinated by the E3 complex LUBAC.
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In contrast, USP15 deubiquitylates TRIM25, preventing the LUBAC dependent degradation of TRIM25 [XREF_BIBR].
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A study has demonstrated that USP15 deubiquitinates TRIM25, thus counteracting the LUBAC dependent degradation of TRIM25.
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USP15 deubiquitinates SMURF2. 7 / 7
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USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination
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In light of the data presented so far we reasoned that USP15 may also directly deubiquitinate SMURF2.
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We now establish that USP15 also directly deubiquitinates the E3 ligase SMURF2, opposing the activity of SMURF2 towards the TbetaR complex.
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Eichhorn and co-workers found that USP15 not only targets the TGF-beta type I receptor complex but also deubiquitinates Smurf2.
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To see if USP15 deubiquitinated SMURF2 in vitro, we purified USP15 and Ub-SMURF2 from extracts of HEK293T cells and proteins were mixed under conditions supporting SMURF2 deubiquitination.
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Here, we demonstrate that apart from targeting the TbetaR complex directly, USP15 also deubiquitinates SMURF2 resulting in enhanced TbetaR stability and downstream pathway activation.
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Our results indicate that USP15 directly deubiquitinates SMURF2 potentially resulting in the inhibition of SMURF2 catalytic activity.
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USP15 deubiquitinates BMPR1A. 7 / 7
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We next asked whether USP15 can deubiquitylate ALK3 in cells.
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Here, we demonstrate that USP15 enhances BMP signalling by associating with and deubiquitylating the BMP type I receptor ALK3.
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USP15 deubiquitylates ALK3.
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Here, we demonstrate that USP15 interacts with and deubiquitylates the type I BMP receptor ALK3.
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It was shown that USP15 interacts with type I BMP receptors, including ALK3, co-localises with ALK3 at the membrane and deubiquitylates ALK3, thereby countering the inhibition of the BMP pathway caused by SMAD6 XREF_BIBR.
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We hypothesized that USP15 deubiquitylates ALK3, thereby opposing the effect of SMAD6 and its associated E3 ubiquitin ligases.
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USP15 deubiquitinates NFKBIA. 7 / 7
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CSN associated USP15 can deubiquitinate IkappaBalpha after TNFalpha mediated stimulation of the NF-kappaB pathway XREF_BIBR.
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In this report, it was postulated that a CSN associated deubiquitinylase (USP15) causes a deubiquitination of IkappaBalpha representing a negative feedback mechanism of IkappaBalpha degradation and NF-kappaB activation.
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No evidence text available
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Schweitzer et al. reported that COP9 signalosome (CSN)-associated USP15 can deubiquitinate IkappaBalpha and regulates the activation of NF-kappaB XREF_BIBR.
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The Cylindroma tumour suppressor protein (CYLD) de-ubiquitinates NEMO and TRAF2 [XREF_BIBR - XREF_BIBR], while USP15 reverses betaTRCP mediated ubiquitination of IkappaBalpha [XREF_BIBR].
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Another report reveals that USP15 deubiquitinates IkappaBalpha and increases its re-accumulation, leading to reduced NF-kappaB activity [XREF_BIBR].
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USP15 deubiquitinates IkappaBalpha and promotes its re-accumulation after TNF-alpha-induced degradation, leading to reduced NF-kappaB activity.
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USP15 deubiquitinates PRPF3. 7 / 7
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These findings suggest that USP15 deubiquitinates PRP3 as well as PRP31 when they are ubiquitinated by E3 ligase although USP15 may have more preference for PRP31.
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Moreover, we found that USP15 and USP4 deubiquitinated substrates PRP31 and PRP3 simultaneously.
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Moreover, it was reported that Sart3, Usp4 and Usp15 form a complex in order to de-ubiquitinate Prp3 and Prp31 simultaneously.
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Deubiquitination of PRP31 and PRP3 by the USP15, SART3, and USP4 complex decreases the affinity towards PRP8 and this regulation is important for the proper splicing of chromosome segregation related genes such as Bub1 and alpha-tubulin.
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However, USP15 deubiquitinated PRP3 in the presence of E3 ligase.
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PRP3 was deubiquitinated by USP15 in the presence of PRP19.
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PRP3 was deubiquitinated by USP4 consistent with a previous report but not by USP15.
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USP15 deubiquitinates TGFBR1. 6 / 6
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For example, the closely related DUBs USP4, USP11 and USP15 have been reported to modulate TGFbeta signalling by deubiquitylating the type I TGFbeta receptor ALK5 [XREF_BIBR - XREF_BIBR].
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UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.
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It has been revealed that the DUBs, UCH37, USP11, and USP15, de-ubiquitinate and stabilize TbetaRI.
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Preliminary results by Ten Dijke and colleagues add weight to this theory whereby they identified that the ability of USP15 to deubiquitinate TbetaRI requires USP4, as USP15 was unable to perform this[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP15 binds to the Smad7 and Smurf2 complex and, like USP4 and USP11, deubiquitinates the TGF-beta type I receptor, thereby maintaining the stability of this receptor and enhancing TGF-beta signalling[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP15 deubiquitinates PRPF31. 6 / 6
1 | 5
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These findings suggest that USP15 deubiquitinates PRP3 as well as PRP31 when they are ubiquitinated by E3 ligase although USP15 may have more preference for PRP31.
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Deubiquitination of PRP31 and PRP3 by the USP15, SART3, and USP4 complex decreases the affinity towards PRP8 and this regulation is important for the proper splicing of chromosome segregation related genes such as Bub1 and alpha-tubulin.
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USP15 regulates dynamic protein-protein interactions of the spliceosome through deubiquitination of PRP31
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Moreover, we found that USP15 and USP4 deubiquitinated substrates PRP31 and PRP3 simultaneously.
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We further confirmed that the modified forms of PRP31 represented a covalent modification of PRP31 with ubiquitin using the denaturing NiNTA-pull down assay and found that USP15 WT but not inactive USP15 C269A led to deubiquitination of PRP31 in the cell.
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Moreover, it was reported that Sart3, Usp4 and Usp15 form a complex in order to de-ubiquitinate Prp3 and Prp31 simultaneously.
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USP15 deubiquitinates TGFB. 5 / 5
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USP15 binds to the SMAD7-SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF-beta receptor (TbetaR-I), leading to an enhanced TGF-beta signal.
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For example, they are involved in the TGF-beta signaling pathway; USP15 deubiquitinates and stabilizes TGF-beta receptor I or receptor activated SMADs, while USP4 regulates the signaling pathway of TGF-beta receptor I and is associated with a poor prognosis in breast cancer.
28088760
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For example, the closely related DUBs USP4, USP11 and USP15 have been reported to modulate TGFbeta signalling by deubiquitylating the type I TGFbeta receptor ALK5 [XREF_BIBR - XREF_BIBR].
24850914
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Moreover, Seoane and colleagues reported that the USP15 gene is amplified in breast cancer, ovarian cancer, and glioblastoma, and that USP15 deubiquitinates and stabilizes type I TGFbeta receptor, thereby enhancing TGFbeta signaling and tumor growth [XREF_BIBR] (XREF_FIG).
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USP15 in this trimeric complex deubiquitinates and stabilizes type 1 TGF-beta receptor, upregulating the TGF-beta signaling and providing a critically pathogenic factor for glioblastoma.
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USP15 deubiquitinates MDM2. 5 / 5
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Considering the USP15-MDM2 direct association and the role of USP15 in stabilizing MDM2 and inhibiting MDM2 ubiquitination in activated T cells (XREF_FIG), we examined whether USP15 directly deubiquitinates MDM2.
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By specifically antagonizing MDM2 auto-ubiquitination, the DUB USP15 prevents NFATc2 dependent gene activation, including IFN-gamma production.
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USP15 deubiquitylates MDM2, an E3 ligase that ubiquitylates and degrades P53 as well as NFATc2.
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Under normal condition, a DUB, Usp15, deubiquitinates MDM2 to inhibit MDM2 degradation, thereby negatively regulating the generation of IFN-gamma-producing Th1 effector T cells.
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USP15 deubiquitinates BARD1. 5 / 5
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Subsequently, USP15 deubiquitinates BARD1 BRCT domain, and promotes BARD1-HP1gamma interaction, resulting in BRCA1 and BARD1 retention at DSBs.
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USP15 deubiquitinates BARD1 BRCT domain.
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XREF_FIG, USP15 deubiquitinated BARD1 BRCT domain in vitro, and promoted BARD1-HP1gamma interaction.
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XREF_FIG, USP15 deubiquitinated the BRCT domain of BARD1 in vitro.
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Because the C terminal of BARD1 is important for its functions in HR, we then investigated if USP15 deubiquitinates BARD1 BRCT domain in vitro and in vivo.
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USP15 deubiquitinates DDX58. 5 / 5
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USP15 specifically deubiquitinates RIG-I by direct physical association and does not interact with other signaling mediators like interferon-beta promoter stimulator 1 (IPS-1), TRAF3, and TBK1 in HEK293 cells.
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Conversely, USP15 and USP4 deubiquitinate TRIM25 and RIG-I, respectively, to stabilize the proteins.
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To further confirm USP15 deubiquitinates polyubiquitination of RIG-I, USP15 siRNAs were transfected into HEK293T cells to knockdown endogenous USP15 expression.
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USP15 specifically removed lysine 63-linked polyubiquitin chains from RIG-I among the essential components in RIG-I-like receptor-dependent pathway.
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Coimmunoprecipitation analysis showed that compared with control siRNA transfected cells, knockdown of USP15 substantially increased RIG-I polyubiquitination in WT ubiquitin and mutant Lys63 transfected cells (XREF_FIG).
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USP15 deubiquitinates NFE2L1. 4 / 4
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Under these experimental conditions, USP15 significantly reduced the smear patterns of 3 x Flag-Nrf1, suggesting that USP15 promotes the deubiquitination of Nrf1.
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Here, we report that USP15 (Ubiquitin-Specific Protease 15) activates Nrf1 in the nucleus by stabilizing it through deubiquitination.
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As a result, these data strongly suggest that USP15 stabilizes endogenous NRF1.We further conducted a ubiquitination assay to examine whether USP15 deubiquitinates Nrf1.
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Taken together, it is fully possible that USP15 deubiquitinates Nrf1 in the nucleus.
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USP15 deubiquitinates KEAP1. 4 / 4
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USP15 deubiquitinates Keap1.
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USP15 activates ubiquitin ligase activity by deubiquitinating Keap1 as its adaptor, promoting the proteasomal degradation of Nrf2.
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Here we report that the deubiquitinating enzyme, USP15, specifically deubiquitinates Keap1, which suppresses the Nrf2 pathway.
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USP15 leads to the deubiquitination of EIF4A1. 4 / 4
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At a mechanistic level, USP15 enhanced the functional properties of HaCaT cells by promoting EIF4A1 deubiquitination.
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Together, these data suggested that USP15 can enhance the migration and proliferation of HaCaT cells by promoting EIF4A1 deubiquitination.
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USP15 Enhances Re-epithelialization Through Deubiquitinating EIF4A1 During Cutaneous Wound Repair.
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USP15 Enhances HaCaT Cell Functionality by Promoting EIF4A1 Deubiquitination.
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USP15 deubiquitinates TP53. 3 / 3
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USP15 deubiquitinates p53.
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To examine whether USP15 can deubiquitinate p53, the effect of USP15 on p53 that had been ubiquitinated by overexpressed MDM2 was determined.
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The mechanism for USP15 to block p53 ubiquitination mediated by MDM2 was analyzed.
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USP15 deubiquitinates TGFBR. 3 / 3
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USP15 in this trimeric complex deubiquitinates and stabilizes type 1 TGF-beta receptor, upregulating the TGF-beta signaling and providing a critically pathogenic factor for glioblastoma.
27893708
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For example, they are involved in the TGF-beta signaling pathway; USP15 deubiquitinates and stabilizes TGF-beta receptor I or receptor activated SMADs, while USP4 regulates the signaling pathway of TGF-beta receptor I and is associated with a poor prognosis in breast cancer.
28088760
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USP15 binds to the SMAD7-SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF-beta receptor (TbetaR-I), leading to an enhanced TGF-beta signal.
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USP15 deubiquitinates SQSTM1. 3 / 3
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At one point, endosomes leave the cloud, which involves the deubiquitination of SQSTM1 and p62 by the deubiquitinating enzyme USP15, and start their fast bidirectional microtubule based journey in the periphery along microtubules and finally the cortical actin cytoskeleton before reaching the cell surface.
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No evidence text available
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At one point, endosomes leave the cloud, which involves the deubiquitination of SQSTM1 and p62 by the deubiquitinating enzyme USP15, and start their fast bidirectional microtubule based journey in the periphery along microtubules and finally the cortical actin cytoskeleton before reaching the cell surface.
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USP15 deubiquitinates FHL1. 3 / 3
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We found a novel protein protein interaction between ubiquitin specific protease 15 (USP15) and skeletal muscle LIM protein 1 (SLIM1) : USP15 and SLIM1 directly bound under cell-free conditions and co-immunoprecipitated from the lysates of the cells, where they were co-expressed; and USP15 deubiquitinated SLIM1, resulting in the increase of protein levels of SLIM1.
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In the present study, we have shown that USP15 interacts with SLIM1 and deubiquitinates SLIM1, leading to the stabilization of SLIM1.
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As we found that SLIM1 was detected in poly-ubiquitinated forms, as well as a non ubiquitinated form, when SLIM1 and Ub were co-expressed in the presence of the proteasome inhibitor MG-132 in HEK293T [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP15 deubiquitinates BMP. 3 / 3
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Here, we demonstrate that USP15 enhances BMP signalling by associating with and deubiquitylating the BMP type I receptor ALK3.
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Here, we demonstrate that USP15 interacts with and deubiquitylates the type I BMP receptor ALK3.
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Herhaus and coworkers showed that USP15 can interact with and deubiquitinate BMP type I receptors, thereby promoting phosphorylation of Smad1 (Herhaus et al., 2014).
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USP15 deubiquitinates H2BC21. 2 / 2
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?Ubp-M may deubiquitinate several critical proteins that are involved in the condensation of mitotic chromosomes, mainly on ubiquitinated proteins of the chromatin such as histones H2A and H2B?
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The U4/U6 recycling factor SART3 has histone chaperone activity and associates with USP15 to regulate H2B deubiquitination.
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USP15 leads to the deubiquitination of DEK. 2 / 2
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USP15 knockdown increased DEK polyubiquitination and canceled the effect of KIF15 overexpression on reducing DEK polyubiquitination.
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USP15 overexpression reduced DEK polyubiquitination.
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USP15 deubiquitinates CARD9. 2 / 2
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USP15 Deubiquitinates CARD9 to Downregulate C-Type Lectin Receptor Mediated Signaling.
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USP15 Deubiquitinates CARD9 to Downregulate C-Type Lectin Receptor-Mediated Signaling.
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USP15 deubiquitinates SMURF2 on K734. 2 / 2
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USP15 deubiquitinates Smurf2 at Lys734, a residue required for Smurf2 transthiolation and catalytic activity.
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These authors performed proteomic analysis and found that USP15 deubiquitinates Smurf2 on Lys734, a residue required for Smurf2 catalytic activity, leading to enhanced TGF-beta signalling (Iyengar et [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP15 deubiquitinates SMAD2_3. 2 / 2
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USP15 has been reported to reverse SMAD2/3 monoubiquitylation, which targets the DNA binding domains of SMAD2/3 and inhibits promoter recognition.
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Upon TGFbeta signaling, Usp15 deubiquitinates Smad2/3, which would lead to p97 dissociation and transcription activation.
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Modified USP15 leads to the deubiquitination of TRIM25. 2 / 2
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In contrast, expression of wild-type USP15, but not its catalytically inactive mutant, reduced the Lys (48)-linked ubiquitylation of TRIM25, leading to its stabilization.
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Furthermore, ectopic expression of USP15 substantially decreased the extent of ubiquitylation of endogenous TRIM25 in virus infected cells (XREF_FIG).
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USP15 leads to the deubiquitination of NFATC2. 2 / 2
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A parallel HEK293 transfection experiment revealed that USP15 did not inhibit the ubiquitination of NFATc2 (XREF_SUPPLEMENTARY).
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These data suggest that USP15 promotes the ubiquitination and degradation of activated NFATc2.
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USP15 leads to the deubiquitination of APC. 2 / 2
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However, it has been reported that the assembly of beta-catenin destruction complex is attributed to CSN mediated deneddylation and also reliant on CSN associated USP15, which catalyzes deubiquitination of APC [XREF_BIBR].
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USP15 deubiquitinates TUT1. 2 / 2
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USP15 deubiquitinates TUT1 associated with RNA metabolism and maintains cerebellar homeostasis.
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USP15 deubiquitinates TUT1 associated with RNA metabolism and maintains cerebellar homeostasis.
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Ubiquitinated USP15 leads to the deubiquitination of DDX58. 2 / 2
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As shown in Fig. 5g, USP15 knockdown greatly enhanced SEV-induced WT and K63-linked polyubiquitination of RIG-I, further confirming USP15-mediated deubiquitination of RIG-I under physiological conditions.
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As shown in XREF_FIG, USP15 knockdown greatly enhanced SEV induced WT and K63 linked polyubiquitination of RIG-I, further confirming USP15 mediated deubiquitination of RIG-I under physiological conditions.
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USP15 deubiquitinates REST. 2 / 2
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XREF_BIBR Changes in the efficiency with which USP15 deubiquitylates nascent REST, and in the cellular availability of REST during interphase, may influence expression of the broader palette of REST target genes.
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USP15 deubiquitinates SMAD7. 1 / 1
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UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.
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USP15 deubiquitinates USP9X. 1 / 1
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UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.
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USP15 deubiquitinates SMAD6. 1 / 1
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USP15 deubiquitinates BRAP. 1 / 1
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USP15 deubiquitinates CHUK. 1 / 1
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USP15 deubiquitinates SMAD2. 1 / 1
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reports have suggested that USP15 acts as a key regulator of TGF-b receptor-signaling pathways by deubiquitinating the TGF-b receptor itself and its downstream transducers receptor-regulated SMADs (R-SMADs), including SMAD1, SMAD2, and SMAD3, thus activating the TGF-b target genes.
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USP15 deubiquitinates SMAD3. 1 / 1
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Multiple mono-ubiquitination of SMAD3 can be removed by USP15 and mono-ubiquitination of SMAD4 seems to be removed by FAM/USP9X.
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USP15 deubiquitinates CYLD. 1 / 1
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UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.
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Modified USP15 leads to the deubiquitination of REST. 1 / 1
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Importantly, expression of GFP-USP15 could also abrogate polyubiquitylation of REST (XREF_FIG, lane 3).
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USP15 deubiquitinates TGFB on R1. 1 / 1
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USP15 Enhances the Proliferation, Migration, and Collagen Deposition of Hypertrophic Scar-Derived Fibroblasts by Deubiquitinating TGF-βR1 In Vitro.
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USP15 deubiquitinates PRKN. 1 / 1
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USP15 does not deubiquitylate Parkin under basal conditions or when cells are treated with mitochondrial depolarizing agents.
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Modified USP15 leads to the deubiquitination of PPIP5K1. 1 / 1
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The overexpression of USP15-WT, but not of the deubiquitinase deficient mutants (USP15-C269A and USP15-H862A), significantly decreased the ubiquitination of RIG-I (XREF_FIG) and did not block ubiquitination of IPS-1 (XREF_FIG), TRAF3 (XREF_FIG) and TBK1 XREF_FIG), illustrating that USP15 has deubiquitination activity for RIG-I.
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Modified USP15 leads to the deubiquitination of NFKBIA. 1 / 1
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An in vitro ubiquitination assay revealed that IkappaBalpha ubiquitination was markedly inhibited by overexpression of CHMP5 or USP15 (XREF_FIG), which is accompanied with pulse-chase labeling experiments showing that IkappaBalpha stability was increased by overexpression of CHMP5 or USP15 (XREF_FIG).
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USP15 deubiquitinates KEAP1 on lysine. 1 / 1
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biopax:reactome
No evidence text available
USP15 deubiquitinates valinomycin on A5. 1 / 1
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However, we found no evidence that USP15 deubiquitinates Parkin in basal conditions or after exposure to valinomycin (Fig. 5A and B).
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USP15 deubiquitinates SMAD1 on lysine. 1 / 1
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No evidence text available
USP15 deubiquitinates CTNNB1. 1 / 1
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Additionally, DUBs USP14, USP15, USP47, and Fam/USP9X have been reported to prevent β-catenin turnover by inhibiting its Ub-proteasomal degradation
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USP15 deubiquitinates USP15. 1 / 1
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UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.
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USP15 deubiquitinates SMAD3 ubiquitinated on K81 on K81. 1 / 1
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In contrast, USP15 deubiquitinates mono-ubiquitinated SMAD3 at K81 and to a lesser degree at K33 and K53 suggesting that USP15 deubiquitinates R-SMADs in the MH1 domain at sites independent of SMURF2 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP15-S678A deubiquitinates BARD1. 1 / 1
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Mechanistically, USP15 S678A mutant failed to deubiquitinate BARD1 in response to MMC treatment, and in turn failed to facilitate the interaction between BARD1 and HP1gamma.
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USP15 deubiquitinates SMAD1. 1 / 1
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reports have suggested that USP15 acts as a key regulator of TGF-b receptor-signaling pathways by deubiquitinating the TGF-b receptor itself and its downstream transducers receptor-regulated SMADs (R-SMADs), including SMAD1, SMAD2, and SMAD3, thus activating the TGF-b target genes.
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USP15 deubiquitinates RBX1. 1 / 1
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USP15 deubiquitinates H2BC10. 1 / 1
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USP15-C269A leads to the deubiquitination of PRPF31. 1 / 1
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We further confirmed that the modified forms of PRP31 represented a covalent modification of PRP31 with ubiquitin using the denaturing NiNTA-pull down assay and found that USP15 WT but not inactive USP15 C269A led to deubiquitination of PRP31 in the cell.
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USP15 deubiquitinates C6orf89. 1 / 1
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Taken together, these data strongly suggest that USP15 directly deubiquitylates BRAP and thereby promotes its stability in mammalian cells.
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Modified USP15 leads to the deubiquitination of RELA. 1 / 1
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Additionally, USP15 overexpression significantly inhibited the ubiquitination of NF-kappaBp65.
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USP15 deubiquitinates SMAD3 on lysine. 1 / 1
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No evidence text available
Modified USP15 leads to the deubiquitination of DDX58. 1 / 1
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The overexpression of USP15-WT, but not of the deubiquitinase deficient mutants (USP15-C269A and USP15-H862A), significantly decreased the ubiquitination of RIG-I (XREF_FIG) and did not block ubiquitination of IPS-1 (XREF_FIG), TRAF3 (XREF_FIG) and TBK1 XREF_FIG), illustrating that USP15 has deubiquitination activity for RIG-I.
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USP15 deubiquitinates X. 1 / 1
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To confirm the deubiquitination of HBx by USP15, we performed an in vivo ubiquitination assay in which HBx was immunoprecipitated and detected by antibody against ubiquitin.
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USP15 deubiquitinates VDAC1. 1 / 1
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Modified USP15 leads to the deubiquitination of IRS2. 1 / 1
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In HEK293cells, Nedd4 overexpression induced IRS-2 ubiquitination, which was decreased by USP15 co-expression while increased by USP15 knockdown.
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USP15 deubiquitinates RNF213. 1 / 1
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Moreover, the USP15 long isoform potently deubiquitylated mysterin and maintained its basal expression level, indicating that alternative exon skipping biases the deubiquitylation substrate preference of USP15.
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USP15 deubiquitinates MFN2. 1 / 1
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No evidence text available
USP15-D967H deubiquitinates BARD1. 1 / 1
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At the molecular level, USP15 M861V and D967H disrupted USP15-BARD1 interaction and failed to deubiquitinate BARD1 at the BRCT domain.
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USP15 deubiquitinates thrb. 1 / 1
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USP15 binds to Smurf2 complex and deubiquitinates and stabilizes TRbeta1, and that apparently leads to boosting of TGF-beta-mediated signaling.
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USP15 deubiquitinates RI. 1 / 1
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Co-immunoprecipitation and ubiquitination assays revealed that USP15 interacted with TβRI and deubiquitinated TβRI.
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USP15-M861V deubiquitinates BARD1. 1 / 1
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At the molecular level, USP15 M861V and D967H disrupted USP15-BARD1 interaction and failed to deubiquitinate BARD1 at the BRCT domain.
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USP15 deubiquitinates CASP3. 1 / 1
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USP15 deubiquitinates RORC. 1 / 1
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Knockdown of USP15 or expression of inactive USP15 impaired Th17 differentiation, suggesting a positive role for USP15-mediated deubiquitination of RORγt in Th17 differentiation.
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USP15 deubiquitinates SART3. 1 / 1
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Mutated USP15 deubiquitinates BMPR1A. 1 / 1
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To ask whether FLAG-ALK3 deubiquitylation requires the deubiquitylase activity of USP15, we tested the ability of a catalytically inactive mutant of USP15 (USP15 [C269S]; USP15-DD) to deubiquitylate FLAG-ALK3 in HEK293 cells.
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USP15 deubiquitinates NRF1. 1 / 1
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we report that USP15 (Ubiquitin-Specific Protease 15) activates Nrf1 in the nucleus by stabilizing it through deubiquitination.
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USP15 deubiquitinates SMAD4. 1 / 1
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UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.
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USP15 deubiquitinates SMAD2 on lysine. 1 / 1
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biopax:reactome
No evidence text available

Other Statements

psp cbn pc bel_lc signor biogrid tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi minerva creeds ubibrowser acsn | geneways tees gnbr semrep isi trips rlimsp medscan eidos sparser reach
USP15 affects TGFB
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USP15 activates TGFB.
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USP15 activates TGFB. 10 / 24
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Besides ALK3 , USP15 also interacts with and deubiquitinates monoubiquitinated R-SMADs , causing enhanced TGF-beta and BMP responses in both mammalian cells and Xenopus embryos .
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The DUBs USP4, USP11, USP15, and UCH37 have previously been demonstrated to modulate TGF-beta pathway activity by directly deubiquitinating the TbetaRI, resulting in increased TbetaRI stability (XREF_FIG) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.
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By enhancing TGF-β signaling, USP15 promotes oncogenesis (27).
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In this respect it is important to note that while functional linkage of USP4 to the TGF-beta and SMAD pathway was shown by employing a breast cancer model, USP15 can enhance the tumorigenic effect of TGF-beta in glioblastoma.
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These observations shed light on the function and mechanisms of USP15 mediated modulation of the TGF-beta signalling pathway during wound healing, thus providing a novel potential target for the treatment of refractory wounds.
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Taken together, USP15 can enhance TGFbeta signaling by opposing both TGFbeta receptor polyubiquitination and R-SMAD monoubiquitination, which may contribute to tumor progression.
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38, 39, 40, 41 For example, USP15 upregulates the TGF-beta pathway to promote cell proliferation in glioblastoma pathogenesis.
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Although the mechanisms by which USP15 acts on TGFbeta and BMP signalling proposed in this study differ from those described above, the fundamental observations that USP15 enhances both TGFbeta and BMP signalling are consistent with studies described above XREF_BIBR.
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Conversely, the deubiquitylating enzyme USP15 reverses this modification and restores responsiveness to TGF-beta.
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In this study USP15 was found to potentiate both the TGF-beta pathway and the related BMP pathway by targeting mono-ubiquitinated R-SMADs for deubiquitination.
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Modified USP15 activates TGFB. 1 / 1
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In contrast, ectopic expression of USP15 did not augment TbetaRI levels or overall TGF-beta luciferase activity in SMURF2 CRSP1 cell lines when expressed alone or in combination with SMURF2 C/A indicating that USP15 's role in the TGF-beta pathway is dependent on SMURF2 function (XREF_SUPPLEMENTARY).
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USP15 inhibits TGFB.
| 3
USP15 inhibits TGFB. 3 / 5
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USP15 mediated activation of the TGF-beta pathway is inhibited by a catalytically inactive mutant of SMURF2.
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In this context, to achieve a certain biological outcome, the same DUB can regulate the pathway at different levels (e.g., USP15 and USP4 promote signaling by targeting the TGF-beta receptor and the effector SMADs) or multiple DUBs can act on the same target (e.g., USP15 and OTUB1 promote signaling through stabilizing R-SMADs).
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Downregulation or inhibition of USP15 in a patient derived orthotopic mouse model of glioblastoma decreases TGF-beta activity.
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USP15 affects IFNB1
| 27
USP15 inhibits IFNB1.
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USP15 inhibits IFNB1. 10 / 14
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We found both USP15-HA and USP15-Myc dose-dependently inhibited the SEV- and RIG-I-N-induced activation of IFN-beta.
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Depletion of endogenous USP15 reduced the extent of IFN-beta promoter activation stimulated by GST-RIG-I (2CARD) alone or together with TRIM25 (XREF_FIG).
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The result showed that USP15 caused the dose-dependent inhibition of IFN-β promoter activity (Fig. 2a).
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Cellular ubiquitin specific proteases, USP21, USP3 and USP15, a subfamily of deubiqutinase, remove K63 linked polyubiquitin chains from RIG-I and block it to induce IFN-beta.
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We found both USP15-HA and USP15-Myc dose-dependently inhibited the SEV- and RIG-I-N-induced activation of IFN-β (Supplementary Fig. S5).
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In addition, USP15 dose-dependently inhibited RIG-I-N-triggered IFN-beta-Luc, ISRE-Luc, NF-kappaB-Luc, and IRF3-Luc reporter activities.
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HEK293T cells were transfected with USP15-specific siRNAs or control siRNAs for 24 h. Cells were further infected with SEV or mock infected for 16 h before immunoblots with the indicated antibodies were performed.Figure 2: (a) USP15 inhibited the SEV-induced activation of the IFN-β promoter.
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In addition, USP15 dose-dependently inhibited RIG-I-N-triggered IFN-β–Luc, ISRE–Luc, NF-κB–Luc, and IRF3–Luc reporter activities (Supplementary Fig. S3).
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As observed in HEK293T cells, ectopic expression of USP15 inhibits SEV induced IFN-beta promoter activation, while knockdown of USP15 by siRNA results in upregulation of the activation of IFN-beta, NF-kappaB and IRF3 promoters in A549 cells, as well as the production of IFNB1 and ISGs.
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(b) USP15 inhibited SEV-induced IFN-β mRNA and protein levels.
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USP15-C269A inhibits IFNB1. 2 / 2
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The catalytic mutants USP15 C269A and -H862A, especially USP15-H862A, still dose-dependently inhibited the IFN-beta-Luc, ISRE-Luc, NF-kappaB-Luc, and IRF3-Luc reporter activities.
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The catalytic mutants USP15-C269A and -H862A, especially USP15-H862A, still dose-dependently inhibited the IFN-β–Luc, ISRE–Luc, NF-κB–Luc, and IRF3–Luc reporter activities.
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USP15 decreases the amount of IFNB1.
| 5
USP15 decreases the amount of IFNB1. 2 / 5
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Through real-time RT-PCR, we also found that USP15-WT, USP15-C269A and USP15-H862A inhibit the transcription of endogenous IFNB1 gene and the SEV induced expression of ISGs.
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Through real-time RT-PCR, we also found that USP15-WT, USP15-C269A and USP15-H862A inhibit the transcription of endogenous IFNB1 gene and the SEV-induced expression of ISGs (Supplementary Fig. S4).
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Modified USP15 decreases the amount of IFNB1. 3 / 3
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Overexpression of USP15 inhibited the transcription of IFN-beta.
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The knockdown of USP15 increases RIG-I K63 linked polyubiquitination, enhancing the IFN production, whereas the overexpression of USP15 decreases the type I IFN by blocking the transcription of IFN-beta in HEK293T infected with SeV.
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Overexpression of USP15 inhibited the transcription of IFN-β.
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USP15 activates IFNB1.
| 5
USP15 activates IFNB1. 5 / 5
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However, we also found that co-expression of increasing amounts of USP15-HA and USP15-Myc further enhanced the IFN-β promoter activation stimulated by RIG-I-N and TRIM25 as a function of the dose, in line with the result described by Pauli (Supplementary Fig. S5).
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However, we also found that co-expression of increasing amounts of USP15-HA and USP15-Myc further enhanced the IFN-beta promoter activation stimulated by RIG-I-N and TRIM25 as a function of the dose, in line with the result described by Pauli.
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Coexpression of increasing amounts of Myc tagged USP15 further enhanced the IFN-beta and NF-kappaB promoter activation stimulated by GST-RIG-I (2CARD) and TRIM25 in a dose dependent manner (XREF_FIG).
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Through the comparison we found under the condition that co-expressed with TRIM25, USP15 enhanced the activation of IFN-β.
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Through the comparison we found under the condition that co-expressed with TRIM25, USP15 enhanced the activation of IFN-beta.
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USP15 increases the amount of IFNB1.
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Modified USP15 increases the amount of IFNB1. 1 / 1
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Coincident with knockdown experiments, overexpression of USP15 blocked SEV-induced transcription of endogenous IFNB1 gene (323.8 vs 135.4, p = 1.0E-04) and the production of IFN-β proteins (178.2 vs 120.6, p = 3.52E-04) (Fig. 2b).
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USP15 affects REST
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USP15 inhibits REST.
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USP15 inhibits REST. 4 / 12
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Indeed, USP15 depletion impaired the normal periodic accumulation of REST in early G 1, suggesting that it plays an important role in cellular REST homeostasis.
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We conclude that depletion of USP15 reduced the level of nuclear 220 kDa REST in both HEK-293T and A549 cells, not through accelerating its degradation, but rather through diminishing the supply of newly synthesized REST available to replenish its levels.
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However, USP15 depletion does not destabilize pre-existing REST, but rather specifically impairs de novo REST synthesis.
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Although one USP15 targeting sequence did diminish the REST transcript, importantly this was not observed with another individual siRNA that also reduced REST protein abundance, or with the siRNA pool used in the initial screen.
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USP15 activates REST.
| 8
USP15 activates REST. 8 / 11
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To establish whether the deubiquitylase activity of USP15 could rescue REST, we employed HEK-293T cells, which, unlike A549 cells, are amenable to high efficiency plasmid transfection.
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While USP15 does not antagonize beta-TrCP-mediated REST degradation, is required for the rapid replenishment of REST upon mitotic exit for the beginning of the new cell cycle.
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The other key observation was that in conditions where translation was inhibited, USP15 knockdown failed to accelerate REST degradation.
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We show that USP15 does not antagonize degradation of pre-existing REST or protect phosphorylated REST at mitosis.
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Through reversing the ubiquitylation of newly synthesized REST, USP15 allows nuclear REST to be replenished in early G 1 after mitotic exit.
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DUBs " found in translation " : USP15 controls stability of newly synthesized REST.
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Instead, the physiological role of USP15 is to promote new REST synthesis to restore its cellular level at mitotic exit.
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Depletion of USP15 failed to accelerate the turnover of REST under conditions where translation was inhibited (XREF_FIG).
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USP15 increases the amount of REST.
| 2
USP15 increases the amount of REST. 2 / 3
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Inhibition of the proteasome with epoxomicin could rescue REST levels following USP15 depletion with two independent siRNAs (XREF_FIG, compare lane 5 with 6, and lane 7 with 8), suggesting this was indeed an effect on protein turnover.
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However, we noticed that the level of 220 kDa REST was not restored by GFP-USP15, suggesting that the degradation of this mature form was not directly antagonized.
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USP15 affects apoptotic process
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USP15 inhibits apoptotic process.
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USP15 inhibits apoptotic process. 10 / 17
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USP15 overexpression inhibits MM cell apoptosis.
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Overexpression of USP15 promoted proliferation and inhibited apoptosis, and these effects were inhibited by PDTC treatment.
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Overexpression of Ubiquitin-Specific Protease15 ( USP15 ) Promotes Tumor Growth and Inhibits Apoptosis and Correlated With Poor Disease-Free Survival in Hepatocellular Carcinoma .
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In conclusion, our results indicate that NF-κBp65 is involved in the regulation of USP15 in MM proliferation and apoptosis and that USP15 inhibits MM apoptosis through activating a feedback loop with NF-κBp65.
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USP15 inhibits multiple myeloma cell apoptosis through activating a feedback loop with the transcription factor NF-kappaBp65.
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It has been reported that the reduced RBM5 and USP15 expressions result in tumor cell proliferation [XREF_BIBR, XREF_BIBR] and induce tumor cell apoptosis [XREF_BIBR], respectively.
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These results suggest that targeting USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses and, thus, have important clinical applications.
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These findings suggest that targeting USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses.
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PDTC treatment inhibits USP15 overexpression induced MM cell proliferation and apoptosis inhibition.
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Zhou et al. noted that depletion of USP15 in multiple myeloma enhanced the NFkappaB transcriptional activity and reduced the rate of apoptosis.
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USP15 activates apoptotic process.
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USP15 promotes the apoptosis of degenerative nucleus pulposus cells by suppressing the PI3K and AKT signalling pathway.
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Under these standard T cell differentiation conditions, USP15 deficient and wild-type T cells were similar in differentiation and proliferation, although the USP15 deficient T cells had moderately enhanced apoptosis compared to wild-type T cells (XREF_SUPPLEMENTARY).
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Crucially, ectopic expression of either p53 R175H or USP15 promoted p53 triggered apoptosis in human cervical cancer cells.
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The findings that USP15 deficiency promotes T cell activation and cancer cell apoptosis indicated that inhibition of USP15 might suppress tumor growth both via a tumor cell-intrinsic mechanism and by enhancing the anti-tumor host defense.
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USP15 affects TRIM25
| 1 11
USP15 activates TRIM25.
| 9
USP15 activates TRIM25. 9 / 12
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Our study also revealed some of the details about how and when during viral infection USP15 modulates TRIM25 activity.
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USP15 deubiquitinates LUBACmediated K48-linked ubiquitination of TRIM25 and promotes the protein stability of TRIM25, there by promoting K63-linked ubiquitination of RIG-I and potentiating virus-triggered expression of type I IFN genes [82] .
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Ubiquitin specific peptidase 15 (USP15) could enhance the stabilization of TRIM25 by counteracting its K48 linked ubiquitylation and thereby positively regulate the TRIM25-RIG-I signaling pathway.
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On the other hand, USP4 and USP15 enhance the stability of RIG-I and TRIM25, respectively, by proteolytically cleaving K48 linked ubiquitylation from these molecules XREF_BIBR, XREF_BIBR.
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Furthermore, ectopic expression of USP15 enhanced the TRIM25- and RIG-I-dependent production of type I IFN and suppressed RNA virus replication.
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Ubiquitin specific protease 15 (USP15) prevents LUBAC-dependent degradation of TRIM25 which also promotes RIG-I signaling pathways [151].
| PMC
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In contrast, endogenous TRIM25 protein abundance did not change in USP15 expressing cells, suggesting that USP15 prevented the degradation of TRIM25.
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Through a combination of biochemical and molecular assays, we further found that USP15 removed Lys 48 -linked ubiquitin moieties from TRIM25, thereby preventing TRIM25 degradation by the proteasome.
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In addition, the ectopic expression of USP15 enhances the TRIM25- and RIG-I-mediated production of type I IFN and thus suppresses RNA virus replication, whereas the depletion of USP15 causes decreased IFN production and markedly enhanced viral replication (85).
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USP15 inhibits TRIM25.
| 1 1
USP15 inhibits TRIM25. 2 / 5
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The DENV and human papillomavirus Type 16 ( HPV16 ) suppress TRIM25 activity by USP15 to attenuate RIG-I signaling .
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During human papillomavirus (HPV) infection, the E6 oncoprotein interacts with TRIM25 and ubiquitin-specific peptidase 15 (USP15), which enhances TRIM25 degradation and subsequently inhibits RLR/MAVS signaling.
| PMC
USP15 increases the amount of TRIM25.
| 1
USP15 increases the amount of TRIM25. 1 / 1
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USP15 enhances the TRIM25- and RIG-I-mediated expression of type I IFN.
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USP15 affects Interferon
| 2 15
USP15 inhibits Interferon.
| 1 9
USP15 inhibits Interferon. 10 / 11
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In a study using HEK293T cells and Sendai virus (SeV), knockdown of the gene transcribing USP15 resulted in upregulation of type I IFN, while overexpression of USP15 decreased type I interferon as USP15 showed dose dependent inhibition of IFN-beta [XREF_BIBR].
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However, when expressed alone, USP15 inhibited the IFN signaling pathway.
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Reminding us USP15 may antagonize type I IFN induction independently of catalytic activity.
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We will discuss them one by one.In a study using HEK293 T cells and Sendai virus (SeV), knockdown of the gene transcribing USP15 resulted in upregulation of type I IFN, while overexpression of USP15 decreased type I interferon as USP15 showed dose-dependent inhibition of IFN-β [16] .
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Although we can not rule out the possibility that USP15 exerts its effects in a third uncharacterized manner, the data in this study demonstrate that USP15 sequesters the interaction between RIG-I and IPS-1, shedding light on the mechanisms underlying the catalytic-activity-independent antagonism of IFN by USP15.
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These findings taken together support the hypothesis that USP15 function as a negative regulator of IFN signaling.We also assessed whether USP15 deubiquitinase activity is required for its inhibitory role in SEV-induced IFN induction.
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Knockdown of USP15 results in upregulation of type I IFN .
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We will discuss the DUBs that influence the pathways of interferons (IFN), tumor necrosis factors (TNF), TNF-related apoptosis-inducing ligand (TRAIL), interleukins (IL) and chemokines.In a study using HEK293 T cells and Sendai virus (SeV), knockdown of the gene transcribing USP15 resulted in upregulation of type I IFN, while overexpression of USP15 decreased type I interferon as USP15 showed dose-dependent inhibition of IFN-β [16].
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To verify the specific mechanism of USP15 mediated IFN inhibition, we identified the DUB activity site His862 of USP15 in vivo and in vitro, and we presented evidence that USP15 functions as a RIG-I deubiquitinase and specifically removes Lys63 linked polyubiquitin chains.
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These results together suggested that both USP15 constructed in two different expression plasmids inhibited the production of IFN.
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USP15 activates Interferon.
| 1 4
USP15 activates Interferon. 5 / 5
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Furthermore, ectopic expression of USP15 enhanced the TRIM25- and RIG-I-dependent production of type I IFN and suppressed RNA virus replication.
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In addition, the ectopic expression of USP15 enhances the TRIM25- and RIG-I-mediated production of type I IFN and thus suppresses RNA virus replication, whereas the depletion of USP15 causes decreased IFN production and markedly enhanced viral replication (85).
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Knockdown of USP15 results in upregulation of type I IFN.
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In addition, we demonstrated that in contrast to USP15 de-ubiquitinating (DUB) activity, USP15 mediated inhibition of IFN signaling was not abolished by mutations eliminating the catalytic activity, indicating that a fraction of USP15 mediated IFN antagonism was independent of the DUB activity.
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In addition , the ectopic expression of USP15 enhances the TRIM25 - and RIG-I-mediated production of type I IFN and thus suppresses RNA virus replication , whereas the depletion of USP15 causes decreased IFN production and markedly enhanced viral replication ( 85 ) .
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USP15 increases the amount of Interferon.
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USP15 increases the amount of Interferon. 2 / 2
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Several other DUBs have also been implicated in the regulation of RIG-I ubiquitination and virus induced type I IFN expression; these include A20, USP3, USP15, USP21, and USP25 XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.
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USP15 enhances the TRIM25- and RIG-I-mediated expression of type I IFN.
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TGFB affects USP15
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TGFB activates USP15.
| 14
TGFB activates USP15. 10 / 14
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Upregulation of USP15 by TGF-beta was also observed in HEK293 cells (XREF_FIG).
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It is known that TGFbeta upregulates the protein translation of USP15 in a PI3K and Akt dependent manner.
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TGF-beta promotes the translation of USP15 through activation of mammalian target of rapamycin by the phosphoinositide 3-kinase/AKT pathway.
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In the presence MG132 that inhibits proteasome activity, treatment with TGF-beta increases USP15 production (XREF_FIG).
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Taken together, TGF-beta enhanced USP15 production was due to upregulation of its translation and not by suppression of USP15 degradation.
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TGF-beta upregulates the translation of USP15 through a non smad pathway.
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31 We have also demonstrated that TGF-beta signaling can upregulate USP15 synthesis (XREF_FIG).
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TGF-beta promotes USP15 production.
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Upregulation of USP15 by TGF-beta is not due to an increase in USP15 transcription.
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In this study, we demonstrate that TGF-beta can upregulate the translation of USP15 through the PI3K and AKT pathway, in turn resulting in stabilizing p53 through deubiquitination.
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TGFB increases the amount of USP15.
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TGFB increases the amount of USP15. 2 / 3
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Monoubiquitination of R-SMADs prevents the R, SMAD, and SMAD4 complex binding with the DNA, while USP15 reverses the modification and promotes TGFbeta dependent transcription.
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In addition, in the presence of cycloheximide that blocks translation, the levels of USP15 increased by TGF-beta treatments were blocked (XREF_FIG).
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USP15 affects NFE2L2
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USP15 inhibits NFE2L2.
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USP15 inhibits NFE2L2. 7 / 8
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Taken together, these data indicate that USP15 inhibition protects podocytes from HG-induced injury by enhancing Nrf2 activation via Keap1.
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Taken together, these results further demonstrate that USP15 negatively regulates the Nrf2 antioxidant response.
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Myc-USP15 inhibited the activity of Nrf2 in a concentration dependent manner (XREF_FIG).
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USP15 negatively regulates Nrf2 through deubiquitination of Keap1.
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USP15 inhibits the transcriptional activity of Nrf2 and the Nrf2 dependent antioxidant response.
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In accordance, the deubiquitinating enzyme USP15 negatively regulates Nrf2 through deubiquitination of Keap1 [XREF_BIBR].
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USP15 increases the degradation of Nrf2 by stabilizing the Cul3-Keap1-E3 ubiquitin ligase complex.
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USP15 decreases the amount of NFE2L2.
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USP15 decreases the amount of NFE2L2. 7 / 7
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We found that USP15 is unable to inhibit Nrf2 protein levels in the absence of Keap1 (XREF_FIG, lanes 3-4).
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USP15 inhibits Nrf2 protein levels and expression of its target genes.
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Further investigation showed that inhibition of USP15 enhanced the activation of NF-E2-related factor 2 (Nrf2) and expression of Nrf2 target genes in HG-simulated podocytes.
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In addition, USP15 is unable to inhibit Nrf2 protein levels when the seven lysine residues in the Neh2 domain required for ubiquitination by the Keap1-Cul3-E3 ligase complex are mutated (Nrf2-K7) (XREF_FIG, lanes 3-4), or when the Neh2 domain is deleted (XREF_FIG, lanes 5-6).
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Taken together these results demonstrate the mechanism by which USP15 leads to decreased Nrf2 protein levels : USP15 is able to stabilize the Cul3-Keap1-E3 ligase complex through deubiquitination of Keap1, resulting in increased E3 ligase activity and ubiquitination of Nrf2, which ultimately leads to degradation of the Nrf2 protein.
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These results indicate that USP15 may inhibit Nrf2 protein expression and thus, its activity, by increasing Nrf2 protein degradation.
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Conversely, when the Neh6 domain of Nrf2 is deleted, USP15 is still able to inhibit Nrf2 protein expression (XREF_FIG, lanes 7-8).
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USP15 activates NFE2L2.
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USP15 activates NFE2L2. 1 / 1
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Inhibition of USP15 and subsequent activation of NRF2 leads to redox perturbations in AML cells, coincident with impaired leukemic cell function.
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USP15 affects TP53
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USP15 activates TP53.
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USP15 activates TP53. 9 / 10
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Overexpression of USP15 increased the half-life of endogenous p53, but overexpression of the inactive USP15 C269S failed to increase the half-life of p53 (XREF_FIG).
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Conversely, whereas USP4 and USP15 target p53 inhibiting ligases ARF-BP1 [XREF_BIBR] and MDM2 [XREF_BIBR], respectively, USP11 stabilizes p53 [XREF_BIBR] as well as several other tumor suppressors including PML [XREF_BIBR], BRCA2 [XREF_BIBR] and Mre11 complex members MRE11 & RAD50 [XREF_BIBR].
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USP15 can stabilize p53 through deubiquitination (XREF_FIG) and upregulate the p53 transcriptional activity, in turn promoting the expression of p21 (XREF_FIG).
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Crucially, ectopic expression of either p53 R175H or USP15 promoted p53 triggered apoptosis in human cervical cancer cells.
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Western blot analysis indicated that overexpression of Flag-USP15 increased the stability of p53, in turn leading to an increased expression of p21, a p53 regulated target gene (XREF_FIG).
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29 USP15 knockdown abolished p53 stabilization by TGF-beta signaling (XREF_FIG) and suppressed the transcriptional activity of p53 (XREF_FIG).
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TIFAB Regulates USP15 Mediated p53 Signaling during Stressed and Malignant Hematopoiesis.
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Our results confirmed a previous report that overexpression of USP15 can upregulate the transcriptional activity of p53.
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USP15 knockdown disrupted p53 stability and p21 synthesis mediated by TGF-beta, indicating that TGF-beta modulated p53 stability through upregulation of USP15 synthesis (XREF_FIG).
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USP15-C269S activates TP53. 2 / 2
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Overexpression of an inactive USP15 C269S did not increase the stability of p53 (XREF_FIG).
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Overexpression of USP15 increased the half-life of endogenous p53, but overexpression of the inactive USP15 C269S failed to increase the half-life of p53 (XREF_FIG).
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USP15 increases the amount of TP53.
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Modified USP15 increases the amount of TP53. 2 / 2
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However, co-overexpression of USP15 in the p53 knockdowned cells can increase the levels of p53 (XREF_FIG).
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In addition, co-overexpression of shRNA-insensitive USP15 cDNA in USP15 knockdowned cells can increase the levels of the recombinant USP15 and, in turn, upregulate the levels of the cellular p53 (XREF_FIG).
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USP15 decreases the amount of TP53.
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USP15 decreases the amount of TP53. 1 / 1
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Nevertheless, considering that USP15 maintains MDM2 protein level and negatively regulates p53 dependent gene transcription and apoptosis in cancer cells, USP15 may represent an excellent drug target for efficient cancer therapy [XREF_BIBR, XREF_BIBR].
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Modified USP15 decreases the amount of TP53. 1 / 1
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In addition, co-overexpression of shRNA-insensitive USP15 cDNA in USP15 knockdowned cells can increase the levels of the recombinant USP15 and, in turn, upregulate the levels of the cellular p53 (XREF_FIG).
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Nef affects USP15
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Nef inhibits USP15.
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Nef inhibits USP15. 9 / 9
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Further, while the amount of intracellular Nef and USP15 was mutually regulated, USP15 mediated degradation of Nef was stronger than Nef mediated USP15 degradation, implying that USP15 could be employed to knock out Nef, a molecule essential to pathogenicity, within HIV-1 infected cells.
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Further, while the amount of intracellular Nef and USP15 was mutually regulated, USP15 mediated degradation of Nef was stronger than Nef mediated USP15 degradation, implying that USP15 could be employ[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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These data collectively demonstrated that stability of Nef and USP15 is regulated reciprocally, and that USP15 mediated degradation of Nef was more pronounced than Nef mediated degradation of USP15.
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Further, Nef, but not Gag, degraded USP15, suggesting that reciprocal degradation of Nef and USP15 could play a central role in coordinating decay of viral proteins and hence HIV-1 replication, underlining the dynamic competition between the molecular determinants of the infecting HIV-1 and the infected host cells.
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Taken together, the results show that Nef and USP15 declines were due to expressed protein degradation, and USP15 mediated degradation of Nef was much stronger than Nef mediated USP15 degradation.
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These data indicate that Nef expressed from the wt-HIV-1-, but not from Deltanef-HIV-1-replicating cells, degraded USP15, lowering the amount of intracellular USP15, which in turn vitiated USP15 induc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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These data indicate that Nef expressed from the wt-HIV-1-, but not from Deltanef-HIV-1-replicating cells, degraded USP15, lowering the amount of intracellular USP15, which in turn vitiated USP15 induced degradation of viral proteins and thereby HIV-1 replication, where Nef degrades USP15, but USP15 mediated Nef degradation is more potent (XREF_FIG).
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These data establish that USP15 mediated p24 degradation is achieved via both endosomal and proteosomal degradation.These data collectively demonstrated that stability of Nef and USP15 is regulated re[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Taken together, the results show that Nef and USP15 declines were due to expressed protein degradation, and USP15 mediated degradation of Nef was much stronger than Nef mediated USP15 degradation (XREF_FIG).
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Nef activates USP15.
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Nef activates USP15. 6 / 6
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Our data showed that as the amount of pHNef was increased from 0 to 4 mug, the USP15 levels gradually decreased in a dose dependent manner (XREF_FIG) without changes to the amount of beta-actin (XREF_FIG), indicating that Nef expression caused the intracellular USP15 diminution.
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Accordingly, USP15 degraded key intracellular viral proteins, such as Nef and Gag in the HIV-1-replicating cells and thereby significantly impaired HIV-1 replication, and Nef induced decay of USP15 wh[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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However, we did not detect significant amounts of USP15 in the nucleus.The above data demonstrated that Nef and USP15 degraded reciprocally and that USP15 mediated degradation of Nef was very pronounc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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The above data demonstrated that Nef and USP15 degraded reciprocally and that USP15 mediated degradation of Nef was very pronounced, compared with Nef mediated decay of USP15.
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Accordingly, USP15 degraded key intracellular viral proteins, such as Nef and Gag in the HIV-1-replicating cells and thereby significantly impaired HIV-1 replication, and Nef induced decay of USP15 which is known to stabilize cellular proteins.
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Our data showed that as the amount of pHNef was increased from 0 to 4 mug, the USP15 levels gradually decreased in a dose dependent manner without changes to the amount of beta-actin, indicating that [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP15 affects NFkappaB
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USP15 activates NFkappaB.
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USP15 activates NFkappaB. 10 / 10
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USP15 is also reported to activate NF-kappaB signaling by deubiquitination and stabilization of the transcription factor NF-kappaB p65 , which inhibits apoptosis and induces cell proliferation in multiple myeloma [ 68 ] .
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Zhou et al. noted that depletion of USP15 in multiple myeloma enhanced the NFkappaB transcriptional activity and reduced the rate of apoptosis.
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In contrary, another study found no interaction between USP15 and IkappaBalpha, and it was proposed that USP11 inhibits the ubiquitination and degradation of IkappaBalpha in the early stage while USP15 functions at a later time point in the TNFalpha induced NF-kappaB activation XREF_BIBR.
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Similarly, we observed that increasing quantities of USP15 caused the inhibition of SEV induced activation of ISRE (XREF_FIG), NF-kappaB (XREF_FIG), and IRF3 (XREF_FIG) promoters, additionally, the expression of ISGs.
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USP15 potentiates NF-kappaB activation by differentially stabilizing TAB2 and TAB3.
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Overexpression of USP15 potentiated TNFalpha- or IL-1beta-triggered NF-kappaB activation and downstream genes transcription, whereas knockdown of USP15 had opposite effects.
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As shown in XREF_FIG, co-expression of USP15 enhanced the AP-1, AP-2, AP-3, SP-1 and NF-kappaB signal pathways transactivated by ectopically expressed HBx although these signal pathways were also affected to a lesser extent by USP15 overexpression alone (XREF_FIG).
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However, Sun et al. found no interaction between USP15 and IkappaBalpha, and proposed that USP11 inhibits the ubiquitination and degradation of IkappaBalpha in the early stage, whereas USP15 functions at a later time point in the TNFalpha induced NF-kappaB activation XREF_BIBR.
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Collectively, USP15 positively regulates TNFalpha- and IL-1beta-triggered NF-kappaB activation by distinct mechanisms, which reflects the potential nonredundant roles of TAB2 and TAB3.
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Coexpression of increasing amounts of Myc tagged USP15 further enhanced the IFN-beta and NF-kappaB promoter activation stimulated by GST-RIG-I (2CARD) and TRIM25 in a dose dependent manner (XREF_FIG).
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USP15 inhibits NFkappaB.
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USP15 inhibits NFkappaB. 4 / 4
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NF-kappaB signaling is negatively regulated by USP11 or USP15 mediated removal of K48 linked ubiquitin chains from IkappaBalpha [XREF_BIBR, XREF_BIBR].
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As shown in XREF_FIG e and XREF_FIG f, knockdown of USP15 increased the activation of NF-kappaB (5.9 vs 12.9, p = 1.92E-04) and IRF3 (15.6 vs 26.5, p = 1.04E-03) through reporter assays.
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In addition, USP15 dose-dependently inhibited RIG-I-N-triggered IFN-beta-Luc, ISRE-Luc, NF-kappaB-Luc, and IRF3-Luc reporter activities.
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Thus , USP15 inhibits NF-kB signaling and its downstream target genes by deubiquitination and stabilization of IkB in mammalian cells [ 33 ] , as illustrated in Figure 2 ( left ) .
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USP15-C269A inhibits NFkappaB. 1 / 1
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The catalytic mutants USP15 C269A and -H862A, especially USP15-H862A, still dose-dependently inhibited the IFN-beta-Luc, ISRE-Luc, NF-kappaB-Luc, and IRF3-Luc reporter activities.
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USP15 affects PRKN
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USP15 inhibits PRKN.
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USP15 inhibits PRKN. 7 / 8
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We wondered whether USP15 knockdown would promote Parkin function in PARK2 mutant PD patient cells with reduced but non-zero Parkin activity.
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Interestingly, USP15 strongly inhibited Parkin-mediated Human Molecular Genetics, 2014, Vol.
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In this regard, USP15 and USP30 were found to antagonize Parkin activity by competing for the common substrates on OMM.
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The OMM localized DUB ubiquitin specific processing proteases USP30 and USP15 antagonize PARKIN activity by cleaving ubiquitin chains on mitochondria.
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In contrast, a recent report demonstrated that in Drosophila the age dependent increase in mitophagy in both muscle and dopaminergic neurons is dependent on PINK1 and Parkin, and the knockdown of USP15 and USP30 rescues mitophagy in Parkin deficient organisms.
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More in detail, USP15 was shown to inhibit CCCP induced mitophagy in Parkin transfected Hela cells depending on its DUB activity and RNAi mediated silencing of USP15 enhanced Parkin mediated mitophagy[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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It was recently shown that knockdown of USP15 enhanced Parkin dependent mitophagy and global upregulation of mitochondrial ubiquitylation upon CCCP [XREF_BIBR].
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USP15 inhibits mutated PRKN. 3 / 3
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These data were also confirmed in vivo in Drosophila, where silencing of Usp15 homolog rescued parkin mutant phenotype, thus showing a genetic interaction between the two genes [XREF_BIBR].
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USP15 knockdown rescues the mitophagy defect of PARK2 mutant PD patient fibroblasts As demonstrated above in HeLa cells ( Fig. 2A) , USP15 knockdown does not enhance mitophagy in the complete absence of Parkin.
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: Knockdown of USP15 rescues the mitophagy defect of PARK2 mutant PD patient fibroblasts.
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USP15 activates PRKN.
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USP15 activates PRKN. 3 / 3
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Furthermore, USP15 KD was able to rescue the mitophagy defect of Parkin and PINK1 mutant PD patient fibroblasts.
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We considered the possibility that USP15 might modulate Parkin function by deubiquitinating Parkin itself.
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Knockdown of the Drosophila homologs of USP15 (CG8334, hereafter called dUSP15) and USP30 (CG3016, hereafter dUSP30) largely rescues the mitochondrial defects of parkin deficient fly muscle in vivo.
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USP15 increases the amount of PRKN.
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USP15 increases the amount of PRKN. 1 / 1
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Moreover, knockdown of USP15 rescues the mitophagy defect of PD patient fibroblasts with PARK2 mutations and decreased Parkin levels.
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USP15 affects nef
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USP15 inhibits nef. 10 / 14
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Further, USP15 degraded not only Nef but also HIV-1 structural protein, Gag, thereby substantially inhibiting HIV-1 replication.
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These data indicate that Nef expressed from the wt-HIV-1-, but not from Deltanef-HIV-1-replicating cells, degraded USP15, lowering the amount of intracellular USP15, which in turn vitiated USP15 induced degradation of viral proteins and thereby HIV-1 replication, where Nef degrades USP15, but USP15 mediated Nef degradation is more potent (XREF_FIG).
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However, we did not detect significant amounts of USP15 in the nucleus.The above data demonstrated that Nef and USP15 degraded reciprocally and that USP15 mediated degradation of Nef was very pronounc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Our data indicated that USP15 clearly induced degradation of Nef and other viral structural protein, Gag, in the repeated experiments.
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Nef could also cause decay of USP15, although Nef mediated degradation of USP15 was weaker than USP15 mediated Nef degradation.
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The above data demonstrated that Nef and USP15 degraded reciprocally and that USP15 mediated degradation of Nef was very pronounced, compared with Nef mediated decay of USP15.
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In parallel, replication of wt- and Deltanef-HIV-1 was significantly impaired by USP15, indicating that USP15 degraded not only Nef but also Gag and thus hampered HIV-1 replication.
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These data establish that USP15 mediated p24 degradation is achieved via both endosomal and proteosomal degradation.These data collectively demonstrated that stability of Nef and USP15 is regulated re[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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These data indicate that Nef expressed from the wt-HIV-1-, but not from Deltanef-HIV-1-replicating cells, degraded USP15, lowering the amount of intracellular USP15, which in turn vitiated USP15 induc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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In parallel, replication of wt- and Deltanef-HIV-1 (XREF_FIG, below A and B, respectively) was significantly impaired by USP15, indicating that USP15 degraded not only Nef but also Gag and thus hampered HIV-1 replication.
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USP15 knockdown significantly inhibited cell proliferation , invasion and epithelial-mesenchymal transition ( EMT ) of GC in vitro , while overexpression of USP15 promoted these processes .
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XREF_FIG, PDTC treatment significantly inhibited the USP15 overexpression induced proliferation of RPMI 8226 and U266 cells by 24.9 and 29.2% at 48h after transfection, respectively.
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USP15 promotes cell proliferation, invasion and EMT progression of GC via regulating the Wnt and beta-catenin pathway, which suggests that USP15 is a novel potential therapeutic target for GC.
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USP15 promotes cell proliferation , invasion and EMT progression of GC via regulating the Wnt / beta-catenin pathway , which suggests that USP15 is a novel potential therapeutic target for GC .
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Overexpression of USP15 promoted proliferation and inhibited apoptosis, and these effects were inhibited by PDTC treatment.
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USP15 enhances the proliferation, migration, invasion, and collagen deposition of hypertrophic scar-derived fibroblasts by deubiquitinating TβRI in vitro.
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38, 39, 40, 41 For example, USP15 upregulates the TGF-beta pathway to promote cell proliferation in glioblastoma pathogenesis.
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PDTC treatment inhibits USP15 overexpression induced MM cell proliferation and apoptosis inhibition.
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USP15 knockdown significantly inhibited cell proliferation, invasion and epithelial-mesenchymal transition (EMT) of GC in vitro, while overexpression of USP15 promoted these processes.
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As such, we hypothesized that USP15 may be able to promote HaCaT cell proliferation in part via altering the EIF4A1 expression.
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USP15 overexpression inhibits cell proliferation and growth in soft agar.
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USP15 affects MDM2
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USP15 activates MDM2.
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USP15 activates MDM2. 5 / 8
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We found that USP15 mediates the stability of MDM2 in both T cells and cancer cells.
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These results suggest that USP15 prevents the ubiquitin dependent degradation of MDM2 in activated T cells.
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Because of the ubiquitin dependent degradation, together with TCR and CD28 stimulation, MDM2 can be transiently down-regulated, and the loss of USP15 greatly promotes the degradation of MDM2 in T cells.
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In both activated T cells and cancer cells, loss of USP15 caused MDM2 degradation.
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We next examined whether USP15 directly targets MDM2.
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USP15 inhibits MDM2.
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USP15 inhibits MDM2. 3 / 6
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Such suicidal MDM2 auto-ubiquination can be blocked by USP15 deubiquitinase that prevents activation of NFATc2 mediated cytokine expression such as production of IFNgamma by Th1 effector T cells.Culli[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Conversely, whereas USP4 and USP15 target p53 inhibiting ligases ARF-BP1 [XREF_BIBR] and MDM2 [XREF_BIBR], respectively, USP11 stabilizes p53 [XREF_BIBR] as well as several other tumor suppressors including PML [XREF_BIBR], BRCA2 [XREF_BIBR] and Mre11 complex members MRE11 & RAD50 [XREF_BIBR].
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In resting T cells, MDM2 was stable even in the absence of USP15; however, the TCR+CD 28 signals stimulated ubiquitin dependent degradation of MDM2, which was negatively regulated by USP15.
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USP15 activates cell differentiation.
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XREF_BIBR, XREF_BIBR Furthermore, deubiquitylating enzyme USP15 mediates K48 linked deubiquitylation of ALK3, to promote ALK3-smad1 signal and BMP induced osteoblast differentiation.
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USP15 stimulates RORgammat activity and Th17 differentiation by enhancing SRC1 recruitment.
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Reduction of USP15 expression from C2C12 myoblast cells inhibited BMP induced osteoblastic differentiation, as judged by the reduction in alkaline phosphatase induction.
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The mutation of Lys 446 to Arg or the deubiquitination of Lys 446 by USP15 promotes NCOA1 recruitment and Th17 differentiation.
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Loss of USP15 in mouse myoblast cells suppressed BMP induced osteoblast differentiation.
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USP15 deficiency promotes the activation of naive CD4 + T cells and their subsequent differentiation into the IFN-gamma-producing Th1 cells.
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We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP induced osteoblast differentiation.
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USP15 inhibits cell differentiation.
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Impaired Th17 differentiation by both inactive C298A and knockdown of USP15 supports the positive role of USP15 in Th17 differentiation.
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Collectively, these results suggest that USP15 negatively regulates naive CD4 + T cell activation and T H 1 differentiation.
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Knockdown of USP15 with two different shRNAs markedly inhibited Th17 differentiation (XREF_FIG, top panels and XREF_FIG) compared to knockdown of a close member of USP15, USP45 (XREF_FIG, bottom panels and XREF_FIG).
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USP15-C298A inhibits cell differentiation. 1 / 1
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In contrast, the inactive USP15 C298A mutant did inhibit Th17 differentiation.
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USP15 affects BMP
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USP15 activates BMP.
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USP15 activates BMP. 7 / 7
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In addition, USP15 also promotes TGF-beta and BMP signaling by opposing monoubiquitylation of R-SMADs, thereby allowing activated R-SMAD-SMAD4 complexes to recognize target promoters [XREF_BIBR].
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Inhibition of USP15 might therefore be employed as a strategy to inhibit BMP signalling.
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Here, our findings show that USP15 DUB activity is essential for BMP signalling, and that loss of USP15 function inhibits BMP signalling in human and mouse cells, as well as during Xenopus embryogenesis.
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Furthermore, they found that USP15 modulates the BMP pathway during Xenopus embryogenesis (Herhaus et al., 2014).
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We therefore asked whether siRNA mediated knockdown of SMAD6 was also able to rescue the inhibition of BMP signalling caused by USP15 depletion.
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Although the mechanisms by which USP15 acts on TGFbeta and BMP signalling proposed in this study differ from those described above, the fundamental observations that USP15 enhances both TGFbeta and BMP signalling are consistent with studies described above XREF_BIBR.
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In this study USP15 was found to potentiate both the TGF-beta pathway and the related BMP pathway by targeting mono-ubiquitinated R-SMADs for deubiquitination.
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USP15 decreases the amount of BMP.
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USP15 decreases the amount of BMP. 4 / 4
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Consistent with this, pretreatment of HEK293 cells with the proteasomal inhibitor bortezomib does indeed rescue BMP induced pSMAD1 levels reduced by USP15 depletion (XREF_FIG b).
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RNAi mediated depletion of USP15 increases ALK3 K48 linked polyubiquitylation, and reduces both BMP induced SMAD1 phosphorylation and transcription of BMP target genes.
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They also showed that depletion of USP15 in Hela cells increased polyubiquitynation of BMP type I receptor, and inhibited BMP mediated Smad1 phosphorylation and BMP target gene transcription.
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Depletion of USP15 reduces BMP induced phosphorylation of SMAD1 and the transcription of BMP-target genes, as well as inhibiting the differentiation of myoblasts into osteoblasts.
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USP15 inhibits BMP.
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USP15 inhibits BMP. 1 / 1
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As depletion of USP15 inhibits BMP signalling, we asked whether elevation of USP15 has the opposite effect.
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USP15 affects DDX58
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USP15 inhibits DDX58.
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USP15 inhibits DDX58. 5 / 7
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USP21 and USP15 remove K63 linked polyubiquitin chains from RIG-I and block the ability of RIG-I to induce IFN-beta XREF_BIBR XREF_BIBR.
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The knockdown of USP15 increases RIG-I K63 linked polyubiquitination, enhancing the IFN production, whereas the overexpression of USP15 decreases the type I IFN by blocking the transcription of IFN-beta in HEK293T infected with SeV.
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USP21 and USP15 remove K63-linked polyubiquitin chains from RIG-I and block the ability of RIG-I to induce IFN-β 24,25 .
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For example, the deubiquitinating enzyme USP15 negatively regulates virusinduced IFN-I production by targeting RIG-I (84).
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In particular, USP3, USP21, USP25 and USP15 have all been shown to directly inhibit RIG-I.
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USP15 activates DDX58.
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USP15 activates DDX58. 1 / 4
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On the other hand, USP4 and USP15 enhance the stability of RIG-I and TRIM25, respectively, by proteolytically cleaving K48 linked ubiquitylation from these molecules XREF_BIBR, XREF_BIBR.
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USP15 affects NFE2L1
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USP15 activates NFE2L1.
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USP15 activates NFE2L1. 8 / 8
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Collectively, we concluded that endogenous USP15 enhances the NRF1 mediated gene expression for proteasome recovery.Finally, we examined the biological relationship between USP15 and other Cap'n ' Col[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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These results clearly suggest that USP15 activates the transcriptional activity of Nrf1.
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These results uncover a new regulatory mechanism that USP15 activates Nrf1 against the beta-TrCP inhibition to maintain proteostasis.
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Moreover, the siRNA mediated knockdown of endogenous USP15 reduced the protein turnover time of endogenous NRF1.
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We also confirmed that other USP15 siRNAs can cause the mRNA induction of NRF1 (data not shown).
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Here, we report that USP15 (Ubiquitin Specific Protease 15) activates Nrf1 in the nucleus by stabilizing it through deubiquitination.
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Hence, these results strongly suggest that USP15 mediates the transcriptional activities of Nrf1.
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A cycloheximide chase experiment also revealed that USP15 increases the turnover time of Nrf1.
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USP15 increases the amount of NFE2L1.
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USP15 increases the amount of NFE2L1. 2 / 2
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Furthermore, we observed that USP15 siRNAs significantly increased the protein expression levels of endogenous NRF1 in HeLa cells.
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Unexpectedly, USP15 siRNA alone induced the mRNA expression of NRF1, thereby augmenting the expression of these proteasomal genes.
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USP15 inhibits NFE2L1.
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USP15 inhibits NFE2L1. 1 / 1
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Under these experimental conditions, USP15 significantly reduced the smear patterns of 3 x Flag-Nrf1, suggesting that USP15 promotes the deubiquitination of Nrf1.
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USP15 affects X
| 10
USP15 activates X.
| 6
USP15 activates X. 6 / 6
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This implied that the association of USP15 with HBx not only increases the stability of HBx but also augments HBx mediated oncogenic signals.
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USP15 enhances the transactivation activity of HBx.
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There results clearly indicate that USP15 attenuates the degradation of HBx.
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We found that USP15 mediated deubiquitylation protects HBx from proteasomal degradation thus increasing the stability and level of HBx protein as well as its transactivation activity.
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USP15 attenuates HBx degradation through deubiquitination of HBx.
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Since we have shown that USP15 is essential for maintaining HBx stability and that USP15 augments HBx mediated oncogenic signals, one inference from our work is that compromising USP15 might be a novel approach to abrogate cellular transformation and serve as a target for anti-cancer therapy.
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USP15 increases the amount of X.
| 4
Modified USP15 increases the amount of X. 1 / 1
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As shown in XREF_FIG, USP15 overexpression significantly increased HBx protein levels in a dose dependent manner.
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USP15 increases the amount of X. 1 / 1
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As shown in XREF_FIG, despite the fact that USP15 dose-dependently increases HBx levels, it did not affect the expression levels of DDB1, a core component of E3 ubiquitin ligase complexes.
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Modified USP15 increases the amount of X. 1 / 1
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However, it should be recognized that while we observed that ectopic expression of USP15 induced a significantly higher levels of HBx than USP5, we can not rule out the involvement of other USPs such as USP4 and USP11 which share 71 and 60% similarity at the amino acid level, respectively XREF_BIBR, contributing to HBx deubiquitylation and subsequent increase of HBx levels.
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USP15 increases the amount of X. 1 / 1
| 1
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USP15 increased HBx protein levels in a dose dependent manner and siRNA mediated knockdown of endogenous USP15 reduced HBx protein levels.
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USP15 affects Ubiquitin
| 7
USP15 inhibits Ubiquitin.
| 5
USP15 inhibits Ubiquitin. 5 / 5
| 5
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The OMM localized DUB ubiquitin specific processing proteases USP30 and USP15 antagonize PARKIN activity by cleaving ubiquitin chains on mitochondria.
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Conversely, the deubiquitinase USP15 antagonizes LUBAC by removing K48linked ubiquitin from TRIM25, leading to its stabilization and thereby promoting RIG-I-mediated antiviral signaling (67) .
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Overexpression of USP15 reduced ubiquitin accumulation on mitochondria, while depletion rescued mitophagy defects in PD patient derived fibroblasts.
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In accordance, the de-ubiquitination assay in LN-229 cells that were transfected with siUSP15, showed that knockdown of endogenous USP15 increased the incorporation of ubiquitin into HECTD1, as compared to the siRNA control cells.
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In resting T cells, MDM2 was stable even in the absence of USP15; however, the TCR+CD 28 signals stimulated ubiquitin dependent degradation of MDM2, which was negatively regulated by USP15.
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USP15 activates Ubiquitin.
| 2
USP15 activates Ubiquitin. 2 / 4
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Depletion of USP15 with two independent siRNA oligos does not interfere with this basic ubiquitylation ladder but promotes the appearance of an additional higher molecular weight ubiquitin smear above the 116-kDa marker that is indicative of the accumulation of distinct polyubiquitylated species of BRAP in the absence of USP15.
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These results suggest that USP15 prevents the ubiquitin dependent degradation of MDM2 in activated T cells.
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USP15 affects IFNG
| 9
USP15 activates IFNG.
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USP15 activates IFNG. 8 / 8
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However, since the development of primary tumors involves a long period of interplays between tumors and the immune system, it has remained unclear how the excessive and chronic production of IFN-gamma by USP15 deficient T cells impacts the development of primary tumors.
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Moreover, excessive IFN-gamma production by USP15 deficient CD4 + T cells promoted the expression of CXCL12 leading to an accumulation of T-bet + Treg cells and CD11b + Gr-1 + MDSC, therefore promoting MCA induced tumorigenesis [XREF_BIBR].
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These findings suggest that T cell intrinsic USP15 deficiency causes excessive production of IFN-gamma, which promotes an immunosuppressive tumor microenvironment, during MCA induced primary tumorigenesis.
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Our present study revealed that in the MCA induced fibrosarcoma model, USP15 deficiency caused hyper-activation of IFN-gamma + T cells, which was associated with formation of a more immunosuppressive tumor microenvironment characterized by upregulated expression of PD-L1 and CXCL12 and enhanced recruitment of Treg cells and MDSCs.
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However, the USP15 deficiency promoted the TCR+CD 28 stimulated production of cytokines, such as interleukin 2 (IL-2) and interferon-gamma (IFN-gamma), in naive CD4 + T cells, as assessed by quantitative real-time RT-PCR (qRT-PCR) (XREF_FIG), intracellular cytokine staining (XREF_FIG) and ELISA (XREF_FIG).
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T cell intrinsic USP15 deficiency promotes excessive IFN-gamma production and an immunosuppressive tumor microenvironment in MCA induced fibrosarcoma.
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To determine the source of the aberrantly higher level of serum IFN-gamma in Usp15 -/- mice, we examined whether the USP15 deficiency promoted IFN-gamma production in T cells or innate immune cells at the tumor site.
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found that USP15 was abundantly expressed in immune cells, and the USP15 deficiency promoted the TCR + CD28 - stimulated production of cytokines, such as interleukin 2 (IL-2) and interferon-gamma in naive CD4 + T cells.
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USP15 decreases the amount of IFNG.
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Modified USP15 decreases the amount of IFNG. 1 / 1
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The accumulation of T-bet + Treg cells in the tumor of Usp15 -/- mice was caused by loss of USP15 in T cells and apparently due to the aberrant expression of IFN-gamma.
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USP15 affects Proteasome
| 5
USP15 activates Proteasome.
| 2
USP15 activates Proteasome. 2 / 4
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Thus, we concluded that USP15 activates proteasome activity through regulating Nrf1 function.We next examined whether the knockdown of endogenous USP15 reduces the NRF1 mediated expression of the prot[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Furthermore, we examined whether USP15 can activate the NRF1 induced endogenous proteasome activity.
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USP15 increases the amount of Proteasome.
| 2
USP15 increases the amount of Proteasome. 2 / 3
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Consequently, USP15 siRNA activated the expression of proteasome genes, such as PSMC4 and PSMA4.
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We surmise that Nrf1 activating stresses facilitate the USP15 mediated deubiquitination rather than the beta-TrCP-mediated ubiquitination, thereby promoting the expression of Nrf1 target genes.The dat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP15 inhibits Proteasome.
| 1
USP15 inhibits Proteasome. 1 / 2
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Nevertheless, USP15 siRNA significantly reduced the induction of proteasome genes by the proteasome inhibitors.
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USP15 affects CD9
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USP15 inhibits CD9. 8 / 8
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These data establish that USP15 mediated p24 degradation is achieved via both endosomal and proteosomal degradation.These data collectively demonstrated that stability of Nef and USP15 is regulated re[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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However, the observed degradation of p24 by USP15 was effectively abrogated, when the transfected cells were treated with MG132 (XREF_FIG), indicating that the proteosomal degradation pathway plays a key role in USP15- mediated degradation of Gag protein.
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Remarkably, the band intensity of p24 degraded by USP15 was visibly weaker, when the cells were treated with Bafilomycin A1.
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These data establish that USP15 mediated p24 degradation is achieved via both endosomal and proteosomal degradation.
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In corroboration, the observed degradation of p24 by USP15 (XREF_FIG) was thoroughly abrogated, when the transfected cells were treated with MG132 (XREF_FIG), indicating that the proteosomal degradation pathway acts on the USP15 mediated degradation of Gag protein.
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In corroboration, the observed degradation of p24 by USP15 was thoroughly abrogated, when the transfected cells were treated with MG132, indicating that the proteosomal degradation pathway acts on the[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Remarkably, the band intensity of p24 degraded by USP15 was visibly weaker (XREF_FIG vs A), when the cells were treated with Bafilomycin A1.
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However, the observed degradation of p24 by USP15 was effectively abrogated, when the transfected cells were treated with MG132, indicating that the proteosomal degradation pathway plays a key role in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP15 affects RELA
| 8
USP15 increases the amount of RELA. 4 / 4
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USP15 promoted NF-kappaBp65 expression through inhibiting ubiquitination.
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USP15 silencing induced MM cell proliferation inhibition, apoptosis, and the expression of nuclear and cytoplasmic NF-kappaBp65, while USP15 overexpression exhibited an inverse effect.
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Moreover, in vivo experiments indicated that USP15 silencing inhibited MM tumor growth and NF-kappaBp65 expression.
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These results suggest that USP15 promotes NF-kappaBp65 expression through deubiquitination.
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Modified USP15 increases the amount of RELA. 4 / 4
| 4
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USP15 overexpression promoted NF-kappaBp65 expression through inhibition of its ubiquitination, whereas NF-kappaBp65 promoted USP15 expression as a positive regulator.
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NF-kappaBp65 positively regulated USP15 expression, whereas USP15 overexpression promoted NF-kappaBp65 expression through deubiquitination of NF-kappaBp65 in MM cells.
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PDTC treatment significantly inhibited USP15 overexpression induced cell proliferation, apoptosis inhibition, and NF-kappaBp65 expression.
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USP15 overexpression promotes the expression of Bcl-2, Bcl-xL, Survivin, and NF-kappaBp65.
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USP15 affects Multiple Myeloma
| 8
USP15 activates Multiple Myeloma.
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To investigate the role of NF-kappaBp65 signaling in USP15 mediated MM cell proliferation and apoptosis, the NF-kappaBp65 signaling inhibitor PDTC was added to MM cell cultures.
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Silencing USP15 inhibited MM cell growth both in vitro and in vivo.
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PDTC treatment inhibits USP15 overexpression induced MM cell proliferation and apoptosis inhibition.
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USP15 knockdown inhibits MM tumor growth and protein expression in vivo.
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USP15 overexpression promotes MM cell proliferation.
30459344
USP15 inhibits Multiple Myeloma.
| 3
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In conclusion, our results indicate that NF-kappaBp65 is involved in the regulation of USP15 in MM proliferation and apoptosis and that USP15 inhibits MM apoptosis through activating a feedback loop with NF-kappaBp65.
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USP15 overexpression inhibits MM cell apoptosis.
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USP15 inhibited MM cell apoptosis through activating a feedback loop with NF-kappaBp65.
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USP15 affects IRF3
| 8
USP15 inhibits IRF3.
| 7
USP15 inhibits IRF3. 5 / 5
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As shown in XREF_FIG e and XREF_FIG f, knockdown of USP15 increased the activation of NF-kappaB (5.9 vs 12.9, p = 1.92E-04) and IRF3 (15.6 vs 26.5, p = 1.04E-03) through reporter assays.
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In addition, USP15 dose-dependently inhibited RIG-I-N-triggered IFN-beta-Luc, ISRE-Luc, NF-kappaB-Luc, and IRF3-Luc reporter activities.
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As shown in Fig. 1e and 1f, knockdown of USP15 increased the activation of NF-κB (5.9 vs 12.9, p = 1.92E-04) and IRF3 (15.6 vs 26.5, p = 1.04E-03) through reporter assays.
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In addition, USP15 dose-dependently inhibited RIG-I-N-triggered IFN-β–Luc, ISRE–Luc, NF-κB–Luc, and IRF3–Luc reporter activities (Supplementary Fig. S3).
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(c–e) USP15 inhibited SEV-induced activation of ISRE and the NF-κB and IRF3 promoters.
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USP15-C269A inhibits IRF3. 2 / 2
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The catalytic mutants USP15 C269A and -H862A, especially USP15-H862A, still dose-dependently inhibited the IFN-beta-Luc, ISRE-Luc, NF-kappaB-Luc, and IRF3-Luc reporter activities.
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The catalytic mutants USP15-C269A and -H862A, especially USP15-H862A, still dose-dependently inhibited the IFN-β–Luc, ISRE–Luc, NF-κB–Luc, and IRF3–Luc reporter activities.
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USP15 activates IRF3.
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USP15 activates IRF3. 1 / 1
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Similarly, we observed that increasing quantities of USP15 caused the inhibition of SEV induced activation of ISRE (XREF_FIG), NF-kappaB (XREF_FIG), and IRF3 (XREF_FIG) promoters, additionally, the expression of ISGs.
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USP15 affects USP15
| 5
USP15 activates USP15.
| 2
USP15 activates USP15. 1 / 3
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Additionally, our results suggest the need to examine whether blockage of endogenous expression of USP15 reverses USP15 mediated degradation of viral proteins and thus the impairment of HIV-1 replication.
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USP15 bound to NOP53 activates USP15. 1 / 1
| 1
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These results taken together indicated that GLTSCR2 interacted with RIG-I and USP15 in a complex to support the activity of USP15 to remove K63 linked polyubiquitin chains from RIG-I, leading to inactivation of RIG-I and blockage of IFN-beta induction.
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USP15 decreases the amount of USP15.
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USP15 decreases the amount of USP15. 1 / 2
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Three distinct siRNAs targeting USP15 and a control siRNA targeting FoxO4 were transfected in HEK293 cells (XREF_FIG a), in which all three USP15 siRNAs caused an approximately 80-90% reduction in USP15 protein levels compared with the FoxO4 control (XREF_FIG a).
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USP15 inhibits USP15.
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USP15 inhibits USP15. 1 / 1
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However, as it is shown here, inhibition of USP15 phosphorylation by curcumin in HeLa cell lysates caused the formation of high-molecular-weight USP15 species, most likely USP15-Ub conjugates.
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USP15 increases the amount of USP15.
| 1
Modified USP15 increases the amount of USP15. 1 / 1
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In addition, co-overexpression of shRNA-insensitive USP15 cDNA in USP15 knockdowned cells can increase the levels of the recombinant USP15 and, in turn, upregulate the levels of the cellular p53 (XREF_FIG).
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Valproic acid affects USP15
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Valproic acid increases the amount of USP15. 7 / 7
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USP15 affects signal transduction
| 2 5
USP15 activates signal transduction.
| 1 3
USP15 activates signal transduction. 4 / 4
| 1 3
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USP15 modulates various signal transduction pathways, including the transforming growth factor-beta (TGF-beta), NF-kappaB, and Wnt-beta-catenin pathways; however, a role for USP15 in the IFN mediated antiviral innate immune response has not yet been described.
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[180] In addition to preventing signaling proteins from degradation by removing K48 linked polyubiquitin chains, USP15 was shown to upregulate RLR signal transduction by indirectly attaching K63 linked polyubiquitin chains on RIG-I.
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] In addition to preventing signaling proteins from degradation by removing K48-linked polyubiquitin chains , USP15 was shown to upregulate RLR signal transduction by indirectly attaching K63-linked polyubiquitin chains on RIG-I .
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These observations shed light on the function and mechanisms of USP15 mediated modulation of the TGF-beta signalling pathway during wound healing, thus providing a novel potential target for the treatment of refractory wounds.
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USP15 inhibits signal transduction.
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USP15 inhibits signal transduction. 3 / 3
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However , when expressed alone , USP15 inhibited the IFN signaling pathway .
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USP15 promotes the apoptosis of degenerative nucleus pulposus cells by suppressing the PI3K and AKT signalling pathway.
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However, when expressed alone, USP15 inhibited the IFN signaling pathway.
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USP15 affects RAF1
| 6
USP15 decreases the amount of RAF1.
| 3
USP15 decreases the amount of RAF1. 3 / 4
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Concordantly, depletion of USP15 in these cells caused a reduction of CRAF expression levels but did not affect the MEK or ERK phosphorylation status (XREF_FIG C).
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Although, USP15 depletion reduced the level of C-RAF, it had no effect on the level of B-RAF and p-MEK in B-RAFV600E harbouring melanoma cells [155].
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RT-PCR analysis of mRNA levels showed that USP15 depletion with two independent oligos causes a reduction of CRAF transcript levels (XREF_FIG A).
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USP15 increases the amount of RAF1.
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USP15 increases the amount of RAF1. 2 / 2
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Rather we found a specific and significant impact of USP15 depletion on a luciferase reporter cloned upstream of the CRAF 3 '-UTR, suggesting that USP15 may modulate CRAF protein levels via an as yet identified mechanism involving its 3 '-UTR.
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Furthermore we are able to demonstrate that USP15 also contributes to the regulation of sustained MAP kinase signaling after acute stimulation by modulating the expression level of the upstream kinase CRAF.
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USP15 activates RAF1.
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USP15 activates RAF1. 1 / 1
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Likewise, USP15 depletion does not alter the ubiquitylation pattern associated with CRAF immunoprecipitates or enhance the turnover of CRAF as assessed by cycloheximide chase experiments (XREF_FIG, B-D).
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USP15 affects mitophagy
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USP15 inhibits mitophagy. 6 / 6
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USP15 knockdown rescues the mitophagy defect of PARK2 mutant PD patient fibroblasts As demonstrated above in HeLa cells ( Fig. 2A ) , USP15 knockdown does not enhance mitophagy in the complete absence of Parkin .
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As demonstrated above in HeLa cells ( Fig. 2A ) , USP15 knockdown does not enhance mitophagy in the complete absence of Parkin .
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Interestingly , USP15 strongly inhibited Parkin-mediated mitophagy , while the other DUBs had no effect ( Fig. 1A and B ) .
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Overexpression of USP15 inhibits mitophagy dependently of its catalytic activity , while depletion of USP15 enhances mitophagy .
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Thus , USP15 knockdown enhanced mitophagy but only in the presence of Parkin .
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USP15 , a deubiquitinase specifically counteracts the parkin-mediated ubiquitination of mitochondria and thus prevents mitophagy , while USP15 knockdown stimulates mitochondrial ubiquitination and age-dependent mitophagy defects in Parkin-deficient muscles and dopaminergic neurons [ 91,106 ] .
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Furthermore, depleting endogenous USP15 enhanced mitophagy in HeLa cells, in a human dopaminergic neuronal cell line and in primary fibroblasts from human patients 150 .
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: Knockdown of USP15 enhances mitophagy in HeLa cells, SH-SY5Y cells and primary human fibroblasts.
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The C269A mutation abolished the inhibitory effect of USP15 on Parkin-mediated mitophagy, indicating that this effect of USP15 required its deubiquitinating activity ( Fig. 1; Supplementary Material, Fig. S2 ).
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The C269A mutation abolished the inhibitory effect of USP15 on Parkin-mediated mitophagy, indicating that this effect of USP15 required its deubiquitinating activity (Fig. 1; Supplementary Data).
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What could be the mechanism for the inhibitory effect of USP15 on Parkin-mediated mitophagy?
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Interestingly, RNAi-mediated knockdown of USP15 in these fibroblasts strongly enhanced mitophagy, so that mitophagy already became demonstrable after 24 h exposure to CCCP or valinomycin (Fig. 2H–K).
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USP15 affects BMPR1A
| 1
USP15 activates BMPR1A. 1 / 6
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USP15 targets ALK3 and BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling.
24850914
USP15 affects immune response
| 6
USP15 inhibits immune response.
| 3
USP15 inhibits immune response. 3 / 3
| 3
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USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2.
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Together, these findings suggest that USP15 inhibition may not only promote cancer cell apoptosis but also boost T cell mediated anti-tumor immunity.
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It is thus possible that inhibition of USP15, along with targeting immunosuppressive regulators of the tumor microenvironment, may induce strong antitumor immunity.
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USP15 activates immune response.
| 3
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These findings indicate that USP15 ablation promotes immunity against transplantable MCA-205, as well as B16, tumors.
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Our previous work demonstrates that USP15 deficiency promotes antitumor immunity in a transplantable B16 melanoma tumor model, which differs from the present findings obtained using the MCA induced primary tumor model.
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USP15 deficiency promotes immunity against transplanted MCA tumors.
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USP15 activates Neoplasm Invasiveness.
| 2 3
USP15 activates Neoplasm Invasiveness. 5 / 5
| 2 3
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The authors hypothesized that USP15 was up-regulated and enhanced the proliferation, migration, invasion, and collagen deposition of hypertrophic scar-derived fibroblasts by deubiquitinating TGF-β receptor I (TβRI) in vitro.
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USP15 knockdown significantly inhibited cell proliferation, invasion and epithelial-mesenchymal transition (EMT) of GC in vitro, while overexpression of USP15 promoted these processes.
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USP15 knockdown significantly inhibited cell proliferation , invasion and epithelial-mesenchymal transition ( EMT ) of GC in vitro , while overexpression of USP15 promoted these processes .
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USP15 promotes cell proliferation , invasion and EMT progression of GC via regulating the Wnt / beta-catenin pathway , which suggests that USP15 is a novel potential therapeutic target for GC .
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USP15 enhances the proliferation, migration, invasion, and collagen deposition of hypertrophic scar-derived fibroblasts by deubiquitinating TβRI in vitro.
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Mutated USP15 inhibits Neoplasm Invasiveness. 1 / 1
| 1
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Strikingly, USP15 mutation blocked central nervous system (CNS) infiltration of peripherally derived myeloid cells and circulating T cells in ECM.
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NOP53 affects USP15
| 6
NOP53 inhibits USP15.
| 3
NOP53 inhibits USP15. 3 / 3
| 3
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It appeared that GLTSCR2 supported and inhibited the ability of USP15, respectively, to remove K63 linked and K48 linked ubiquitination of RIG-I.
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Interestingly, we detected that reduction of endogenous GLTSCR2 resulted in increased USP15 activity in removing K48 linked ubiquitination of RIG-I-N in GLTSCR2 knockdown cells (XREF_FIG, lane 6), whereas GLTSCR2 presence reduced the activity of USP15 in removing K48 linked ubiquitination of RIG-I-N in HEK293T cells (lane 3).
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Interestingly, we detected that reduction of endogenous GLTSCR2 resulted in increased USP15 activity in removing K48-linked ubiquitination of RIG-I-N in GLTSCR2 knockdown cells (Fig. 6d, lane 6) , whereas GLTSCR2 presence reduced the activity of USP15 in removing K48-linked ubiquitination of RIG-I-N in HEK293T cells (lane 3).
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NOP53 activates USP15.
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NOP53 activates USP15. 3 / 3
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Interestingly, we detected that reduction of endogenous GLTSCR2 resulted in increased USP15 activity in removing K48-linked ubiquitination of RIG-I-N in GLTSCR2 knockdown cells (Fig. 6d, lane 6) , whereas GLTSCR2 presence reduced the activity of USP15 in removing K48-linked ubiquitination of RIG-I-N in HEK293T cells (lane 3).
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Our studies revealed a novel role the nucleolar protein GLTSCR2 played in attenuation of IFN-beta, via cytoplasmic translocation to induce the ability of USP15 to deactivate RIG-I.
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Our studies revealed a novel role the nucleolar protein GLTSCR2 played in attenuation of IFN-β , via cytoplasmic translocation to induce the ability of USP15 to deactivate RIG-I.
27824081
USP15 affects E6
| 6
USP15 increases the amount of E6.
| 4
USP15 increases the amount of E6. 3 / 3
| 3
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Knockdown of USP15 by siRNA approach demonstrated that silencing of USP15 decreases the protein levels of E6 significantly.
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Overexpression of USP15 resulted in increased levels of the E6 protein, and the small interfering RNA mediated knockdown of USP15 decreased E6 protein levels.
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Our results indicate that USP15 could increase the level of HPV16 E6 by inhibiting E6 degradation.
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Modified USP15 increases the amount of E6. 1 / 1
| 1
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On the contrary, overexpression of USP15 increases the steady-state levels of E6, suggesting E6 protein could be a target for USP15 directed deubiquitylation [XREF_BIBR].
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USP15 activates E6.
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USP15 activates E6. 2 / 2
| 2
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In addition, HPV16 E6 mRNA was not induced by USP15; therefore, HPV16 E6 appears to be post-translationally regulated.
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USP15 inhibited the degradation of HPV16 E6 in dose dependent manner.
29895155
USP15 affects proteolysis
| 5
USP15 inhibits proteolysis. 5 / 5
| 5
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Further investigation demonstrated the significance of Nef- and USP15 mediated viral and cellular protein degradation with respect to the regulation of the virus life cycle and HIV-1 and host cell competition that is essential for AIDS progression.
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To investigate Nef role in protein degradation, we seek to identify cellular proteins involved in the UPS mediated protein degradation through association with Nef and found ubiquitin specific protease 15 (USP15) which stabilizes proteins by deubiquitylation and by preventing autoubiquitylation of substrates.
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We found that Nef binds to ubiquitin protein ligase E3A (UBE3A and E6AP) which induces protein degradation by attaching Ub to substrates, i.e. Nef associated with two functionally antagonistic proteins in the UPS mediated protein degradation processes, suggesting that UBE3A could be a major cellular component in regulating USP15 mediated viral protein degradation by interacting with Nef and USP15 simultaneously or independently.
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Further investigation demonstrated the significance of Nef- and USP15 mediated viral and cellular protein degradation with respect to the regulation of the virus life cycle and HIV-1 and host cell com[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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To investigate Nef role in protein degradation, we seek to identify cellular proteins involved in the UPS mediated protein degradation through association with Nef and found ubiquitin specific proteas[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
27460547
MYC affects USP15
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MYC decreases the amount of USP15. 5 / 5
5 |
biopax:msigdb
No evidence text available
biopax:msigdb
No evidence text available
biopax:msigdb
No evidence text available
biopax:msigdb
No evidence text available
biopax:msigdb
No evidence text available
USP15 affects TGFBR
| 3
USP15 activates TGFBR.
| 2
USP15 activates TGFBR. 2 / 4
| 2
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USP15 is known to promote stabilization of the TGF-beta receptor and its downstream signal transducers, known as receptor activated SMADS (R-SMADS), thus empowering the TGF-beta signaling [XREF_BIBR, XREF_BIBR].
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Both USP15 and USP4 stimulate TGF-beta signaling by deubiquitylating and stabilizing two key signaling molecules in this pathway, TGF-beta receptor I (TbetaRI) and R-SMADs, suggesting that these two closely related DUBs act in concert to modulate central signaling processes that are involved in oncogenesis and innate immunity.
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USP15 inhibits TGFBR.
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USP15 inhibits TGFBR. 1 / 1
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In this context, to achieve a certain biological outcome, the same DUB can regulate the pathway at different levels (e.g., USP15 and USP4 promote signaling by targeting the TGF-beta receptor and the effector SMADs) or multiple DUBs can act on the same target (e.g., USP15 and OTUB1 promote signaling through stabilizing R-SMADs).
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USP15 affects Parkinson Disease
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USP15 inhibits Parkinson Disease.
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USP15 inhibits Parkinson Disease. 4 / 4
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USP15 knockdown rescues the mitophagy defect of PARK2 mutant PD patient fibroblasts As demonstrated above in HeLa cells ( Fig. 2A) , USP15 knockdown does not enhance mitophagy in the complete absence of Parkin.
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The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy.Loss-of-function mutations in PARK2, the gene encoding the E3 ubiquitin ligase Parkin, are the most frequent cause of recessive Parkinson's disease (PD).
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: Knockdown of USP15 rescues the mitophagy defect of PARK2 mutant PD patient fibroblasts.
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The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy.Loss-of-function mutations in PARK2, the gene encoding the E3 ubiquitin ligase Parkin, are the most frequent cause of recessive Parkinson's disease (PD).
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USP15 activates Parkinson Disease.
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USP15 activates Parkinson Disease. 1 / 1
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Furthermore, USP15 KD was able to rescue the mitophagy defect of Parkin and PINK1 mutant PD patient fibroblasts.
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USP15 affects SMAD2
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USP15 activates SMAD2.
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USP15 activates SMAD2. 2 / 2
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Moreover, Eichhorn et al. (2012) found that inhibition of USP15 decreased TGF-beta type I receptor and -phosphorylated Smad2 concentrations in these cells, thus corroborating the notion that USP15 sta[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Our results indicated that USP15 stimulated TGF-beta and SMAD2 signaling and the cartilage phenotype.
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USP15 activates phosphorylated SMAD2. 1 / 1
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Moreover, Eichhorn et al. (2012) found that inhibition of USP15 decreased TGF-beta type I receptor and -phosphorylated Smad2 concentrations in these cells, thus corroborating the notion that USP15 sta[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP15 increases the amount of SMAD2.
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USP15 increases the amount of SMAD2. 2 / 2
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Similarly, ectopic expression of USP15 and SMURF2 C/A did not enhance p-SMAD2 levels compared with either construct alone (XREF_FIG).
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The authors demonstrated that USP15 knockdown significantly inhibited the proliferation, migration, and invasion of hypertrophic scar-derived fibroblasts in vitro and down-regulated the expression of TβRI, Smad2, Smad3, α-SMA, COL1, and COL3; in addition, USP15 overexpression showed the opposite trends (p < 0.05).
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Mitoxantrone affects USP15
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Mitoxantrone inhibits USP15. 4 / 4
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In addition , it was found that mitoxantrone weakly inhibits the activity of USP15 with an IC50 of 33 muM .
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Crystal structure analysis by Ward et al. highlighted minute differences between the paralogs and noted that mitoxantrone binds and partially inhibits USP15, similar to USP11.
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XREF_BIBR - XREF_BIBR Recently, an anticancer chemotherapy drug, mitoxantrone, has been shown to inhibit USP15, but the potency of USP15 inhibition by this compound is low, and in vivo studies have not been performed.
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Moreover, we report that USP15 is weakly inhibited by the antineoplastic agent mitoxantrone in vitro A USP15 and mitoxantrone complex structure disclosed that the anthracenedione interacts with the S1 ' binding site.
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On the other hand, the aberrant activation of the USP15 deficient T cells appears to promote an immunosuppressive tumor microenvironment that facilitates tumor development during the long period of tumor-immune system interplay.
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The USP15 deficient T cells, likely via excessive production of IFN-gamma, promoted an immunosuppressive tumor microenvironment that suppressed antitumor immunity.
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T cell intrinsic USP15 deficiency promotes excessive IFN-gamma production and an immunosuppressive tumor microenvironment in MCA induced fibrosarcoma.
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USP15 deficient T cells contribute to immunosuppressive tumor microenvironment.
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USP15 affects TET2
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USP15 inhibits TET2. 4 / 4
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USP15 inactivates TET2 and inhibits TET2 binding to substrate DNA.
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Deletion of Usp15 in melanoma stimulates chemokine expression and TILs in a TET2 dependent manner, leading to increased response to immunotherapy and extended life span of tumor bearing mice.
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USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2.
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USP15 catalyzes the removal of K1299 linked monoubiquitin and negatively regulates TET2 activity.
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USP15 affects SMAD
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USP15 inhibits SMAD. 1 / 4
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Consequently, silencing USP15 expression abolishes the recruitment of TGF-beta-activated Smad complexes to regulatory DNA sequences.
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USP15 affects SART3
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USP15 inhibits SART3. 2 / 4
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Taken together, these results provide insights into the regulatory mechanism of human Tip110 degradation by USP15.
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Regulation of ubiquitin-proteasome system mediated Tip110 protein degradation by USP15.
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USP15 affects NFATC2
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USP15 activates NFATC2. 3 / 4
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Therefore, USP15 deficiency promotes NFATc2 activation, causes increased T cell responses and function in antitumor immunity.
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USP15 deficiency enhances NFATc2 activation in naive CD4 + T cells.
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USP15 deficiency did not enhance Nfatc2 mRNA induction, as revealed by a qRT-PCR assay (XREF_SUPPLEMENTARY).
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USP15 affects Carcinogenesis
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USP15 activates Carcinogenesis. 4 / 4
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By enhancing TGF-b signaling , USP15 promotes oncogenesis ( 27 ) .
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By enhancing TGF-β signaling, USP15 promotes oncogenesis (27).
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By enhancing TGF-beta signaling , USP15 promotes oncogenesis ( 27 ) .
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By enhancing TGF-b signaling, USP15 promotes oncogenesis (27) .
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MAX affects USP15
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MAX decreases the amount of USP15. 4 / 4
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USP4 affects USP15
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USP4 activates USP15.
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USP4 activates USP15. 2 / 3
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These data suggest that complex formation of USP15 and USP4 stimulates the enzymatic activity of USP15 and possibly USP4.
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The overexpression of USP4 has been immunohistochemically detected in small cell tumors and adenocarcinomas, supporting the oncogenic potential of USP15 [XREF_BIBR].
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USP4 inhibits USP15.
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USP4 inhibits USP15. 1 / 1
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Unexpectedly, we observed a highly significant reduction in both MEK and ERK phosphorylation after knockdown of USP15, but not USP4, which was most obvious in serum starved cells.
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USP15 affects CD4
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USP15 activates CD4.
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USP15 activates CD4. 3 / 3
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USP15 deficiency promotes the activation of naive CD4 + T cells and their subsequent differentiation into the IFN-gamma-producing Th1 cells.
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However, the USP15 deficiency promoted the TCR+CD 28 stimulated production of cytokines, such as interleukin 2 (IL-2) and interferon-gamma (IFN-gamma), in naive CD4 + T cells, as assessed by quantitative real-time RT-PCR (qRT-PCR) (XREF_FIG), intracellular cytokine staining (XREF_FIG) and ELISA (XREF_FIG).
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found that USP15 was abundantly expressed in immune cells, and the USP15 deficiency promoted the TCR + CD28 - stimulated production of cytokines, such as interleukin 2 (IL-2) and interferon-gamma in naive CD4 + T cells.
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USP15 inhibits CD4.
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USP15 inhibits CD4. 1 / 1
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Collectively, these results suggest that USP15 negatively regulates naive CD4 + T cell activation and T H 1 differentiation.
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RELA affects USP15
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RELA increases the amount of USP15.
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RELA increases the amount of USP15. 2 / 2
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NF-kappaBp65 positively regulated USP15 expression, whereas USP15 overexpression promoted NF-kappaBp65 expression through deubiquitination of NF-kappaBp65 in MM cells.
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USP15 overexpression promoted NF-kappaBp65 expression through inhibition of its ubiquitination, whereas NF-kappaBp65 promoted USP15 expression as a positive regulator.
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RELA activates USP15.
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RELA activates USP15. 2 / 2
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Whereas PDTC treatment significantly decreased the luciferase Firefly and Renilla ratio, LPS treatment significantly increased that ratio when compared to untreated cells, suggesting that NF-kappaBp65 enhances the promoter activity of USP15.
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Conversely, NF-kappaBp65 also enhanced the promoter activity of USP15 and its protein expression.
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N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal inhibits USP15. 3 / 3
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However, the observed degradation of p24 by USP15 was effectively abrogated, when the transfected cells were treated with MG132 (XREF_FIG), indicating that the proteosomal degradation pathway plays a key role in USP15- mediated degradation of Gag protein.
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In corroboration, the observed degradation of p24 by USP15 was thoroughly abrogated, when the transfected cells were treated with MG132, indicating that the proteosomal degradation pathway acts on the[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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However, the observed degradation of p24 by USP15 was effectively abrogated, when the transfected cells were treated with MG132, indicating that the proteosomal degradation pathway plays a key role in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal activates USP15. 1 / 1
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To test if the effect of USP15 on HBx expression is proteasome dependent, Huh7 cells were co-transfected with pHBx-FLAG and pUSP15-myc or USP15 targeting siRNA then treated with the proteasome inhibitor MG132.
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USP15 affects USP4
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USP15 activates USP4. 2 / 3
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Furthermore, they demonstrate that AKT phosphorylation of USP4 enhances the binding of USP4 to USP15 and that overexpression of USP15 increases USP4 stability.
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These data suggest that complex formation of USP15 and USP4 stimulates the enzymatic activity of USP15 and possibly USP4.
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USP15 affects SGCG
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USP15 inhibits SGCG. 3 / 3
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We will discuss the DUBs that influence the pathways of interferons (IFN), tumor necrosis factors (TNF), TNF-related apoptosis-inducing ligand (TRAIL), interleukins (IL) and chemokines.In a study using HEK293 T cells and Sendai virus (SeV), knockdown of the gene transcribing USP15 resulted in upregulation of type I IFN, while overexpression of USP15 decreased type I interferon as USP15 showed dose-dependent inhibition of IFN-β [16].
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We will discuss them one by one.In a study using HEK293 T cells and Sendai virus (SeV), knockdown of the gene transcribing USP15 resulted in upregulation of type I IFN, while overexpression of USP15 decreased type I interferon as USP15 showed dose-dependent inhibition of IFN-β [16] .
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Reminding us USP15 may antagonize type I IFN induction independently of catalytic activity.
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USP15 affects Protein Stability
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USP15 activates Protein Stability. 3 / 3
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Ubiquitin-specific peptidase 15 ( USP15 ) , an important member of deubiquitinating enzymes ( DUBs ) , removes ubiquitin chains from target proteins and promotes protein stability ( Villeneuve et al ., 2013 ) .
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USP15 , an important DUB , removes ubiquitin chains from target proteins and promotes protein stability ( Padmanabhan et al ., 2018 ) .
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A previous study has shown that USP15 interacts with receptor-phosphorylated SMAD proteins ( R-SMADs ) and deubiquitinates transforming growth factor-beta ( TGF-beta ) receptor 1 ( TBR1 ) , thereby promoting protein stability ( Inui et al ., 2011 ) .
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USP15 affects NRF1
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USP15 activates NRF1. 3 / 3
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This study demonstrates a new molecular mechanism of Nrf1 activation by the deubiquitination enzyme USP15 ( Fig. 4 B).
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Here, we report that USP15 (Ubiquitin-Specific Protease 15) activates Nrf1 in the nucleus by stabilizing it through deubiquitination.
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These results uncover a new regulatory mechanism that USP15 activates Nrf1 against the β-TrCP inhibition to maintain proteostasis.
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Bafilomycin A1 affects USP15
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Bafilomycin A1 activates USP15.
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Remarkably, the band intensity of p24 by USP15 was visibly weaker, when the cells were treated with Bafilomycin A1 (compare p24 intensity in XREF_FIG with A), indicating that endosomal degradation inhibitor actually accelerated p24 degradation by unknown mechanism.
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Remarkably, the band intensity of p24 by USP15 was visibly weaker, when the cells were treated with Bafilomycin A1 (compare p24 intensity in Fig. 8 C with A), indicating that endosomal degradation inh[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Bafilomycin A1 inhibits USP15.
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Remarkably, the band intensity of p24 degraded by USP15 was visibly weaker, when the cells were treated with Bafilomycin A1.
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USP15 affects cell growth
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USP15 inhibits cell growth.
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USP15 inhibits cell growth. 2 / 2
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Silencing USP15 inhibited MM cell growth both in vitro and in vivo.
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Ubiquitin Specific Peptidase 15 (USP15) suppresses glioblastoma cell growth via stabilization of HECTD1 E3 ligase attenuating WNT pathway activity.
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USP15 activates cell growth.
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USP15 activates cell growth. 1 / 1
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Silencing USP15 inhibited MM cell growth both in vitro and in vivo.
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USP15 affects Wnt
| 1 1
USP15 activates Wnt.
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USP15 activates Wnt. 1 / 2
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Finally , rescue experiments showed that the effect of USP15 on gastric cancer progression was dependent on Wnt / beta-catenin pathway .
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USP15 inhibits Wnt.
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USP15 inhibits Wnt. 1 / 1
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Taken together, the data provide evidence that USP15 attenuates the canonical WNT pathway mediated by stabilization of HECTD1, supporting a tumor suppressing role of USP15 in a subset of glioblastoma.
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USP15 affects TNF
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USP15 activates TNF.
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USP15 activates TNF. 2 / 2
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Collectively, USP15 positively regulates TNFalpha- and IL-1beta-triggered NF-kappaB activation by distinct mechanisms, which reflects the potential nonredundant roles of TAB2 and TAB3.
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Overexpression of USP15 potentiated TNFalpha- or IL-1beta-triggered NF-kappaB activation and downstream genes transcription, whereas knockdown of USP15 had opposite effects.
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USP15 inhibits TNF.
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USP15 inhibits TNF. 1 / 1
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USP15 knockdown enhanced TNFalpha production upon stimulation with WGP and TDM but not lipopolysaccharide ( LPS ) , demonstrating that USP15 has a specific inhibitory effect on the CARD9-dependent WGP - and TDM-induced pathways but is not involved in the regulation of MyD88 - and TRIF-dependent LPS recognition in primary murine cells .
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USP15 affects MAVS
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USP15 inhibits MAVS.
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USP15 inhibits MAVS. 1 / 2
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During human papillomavirus (HPV) infection, the E6 oncoprotein interacts with TRIM25 and ubiquitin-specific peptidase 15 (USP15), which enhances TRIM25 degradation and subsequently inhibits RLR/MAVS signaling.
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USP15 activates MAVS.
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USP15 activates MAVS. 1 / 1
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During human papillomavirus (HPV) infection, the E6 oncoprotein interacts with TRIM25 and ubiquitin-specific peptidase 15 (USP15), which enhances TRIM25 degradation and subsequently inhibits RLR/MAVS signaling.
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USP15 affects APC
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USP15 activates APC.
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USP15 activates APC. 1 / 2
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Unlike the mechanism of USP15 mediated stabilization of APC, USP15 destabilizes EB1.
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USP15 inhibits APC.
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USP15 inhibits APC. 1 / 1
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CACYBP, which participates in CTTNB1 degradation and USP15, a deubiquitylation enzyme which prevents APC degradation, both were increased in SW480ull cells.
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SMURF2 affects USP15
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SMURF2 activates USP15.
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SMURF2 activates USP15. 2 / 2
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Our results show that SMURF2 is a critical target of USP15 in the TGF-beta pathway and may also explain how USP15 and SMURF2 target multiple complementary protein complexes in other pathways.
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In cells, the UbVs inhibited the deubiquitination of two USP15 substrates, SMURF2 and TRIM25, and the diUbV inhibited the effects of USP15 on the transforming growth factor beta pathway.
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SMURF2 inhibits USP15.
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SMURF2 inhibits USP15. 1 / 1
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Surprisingly, co-expression of catalytically inactive SMURF2 completely abolished the ability of USP15 to activate this reporter (XREF_FIG).
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USP15 affects TOP2A
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USP15 inhibits TOP2A.
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USP15 inhibits TOP2A. 1 / 1
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This is consistent with our data showing that depletion of either USP15 isoform reduces TOP2A accumulation during G2.
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USP15 decreases the amount of TOP2A.
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USP15 decreases the amount of TOP2A. 1 / 1
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USP15 depletion does not affect cell cycle phase distribution within an asynchronous population and did not prevent TOP2A transcription during G2, it did, however, impede accumulation of TOP2A protein (Figs.
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USP15 activates TOP2A.
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USP15 activates TOP2A. 1 / 1
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USP15 promotes accumulation of TOP2A during G2.
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USP15 affects SMAD1
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USP15 decreases the amount of SMAD1.
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Modified USP15 decreases the amount of SMAD1. 1 / 1
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The inhibition of BMP induced pSMAD1 levels by siUSP15-3 was partially rescued by the restoration of FLAG-USP15 overexpression in cells (electronic supplementary material, figure S4).
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USP15 decreases the amount of SMAD1. 1 / 1
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Consistent with this, pretreatment of HEK293 cells with the proteasomal inhibitor bortezomib does indeed rescue BMP induced pSMAD1 levels reduced by USP15 depletion (XREF_FIG b).
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USP15 increases the amount of SMAD1.
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Modified USP15 increases the amount of SMAD1. 1 / 1
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Indeed, overexpression of HA-USP15 in HEK293 cells increased the levels of pSMAD1 in response to BMP signalling (XREF_FIG a), and this was true in both nuclear [XREF_BIBR - XREF_BIBR] and cytoplasmic fractions (XREF_FIG b).
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USP15 affects FHL1
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USP15 inhibits FHL1.
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USP15 inhibits FHL1. 1 / 1
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Fig. 2 A shows that co-expression of USP15, but not the catalytically inactive C269 mutated USP15 [16] markedly reduced the poly-ubiquitinated forms of SLIM1.
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USP15 increases the amount of FHL1.
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Modified USP15 increases the amount of FHL1. 1 / 1
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Furthermore, co-expression of USP15 increased the protein levels of SLIM1 depending on its deubiquitinating activity, suggesting an escape from the proteasomal degradation.
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USP15 activates FHL1.
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USP15 activates FHL1. 1 / 1
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Thus, overexpression of USP15 increases protein levels of the two isoforms of SLIM1, and the increase of isoform 2 is partly due to the stimulation of de novo synthesis.We have shown that cardiac spec[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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YneF affects USP15
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Modified yneF decreases the amount of USP15. 2 / 2
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Paralleling the pHNef expression (lane 2, Fig. 2 C), transfection of pYNef expressing R-tropic nef (YU2 strain) of HIV-1 reduced the amount of USP15 (lane 3, Fig. 2 C), establishing that the observed [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Paralleling the pHNef expression (lane 2, XREF_FIG), transfection of pYNef expressing R-tropic nef (YU2 strain) of HIV-1 reduced the amount of USP15 (lane 3, XREF_FIG), establishing that the observed decreases of USP15 were not just strain specific but were common to different strains of HIV-1 Nef.
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Phenylmercury acetate increases the amount of USP15. 2 / 2
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Cobalt dichloride affects USP15
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Cobalt dichloride increases the amount of USP15. 2 / 2
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USP15 affects sev
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USP15 inhibits sev. 2 / 2
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We found both USP15-HA and USP15-Myc dose-dependently inhibited the SEV- and RIG-I-N-induced activation of IFN-beta.
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We found both USP15-HA and USP15-Myc dose-dependently inhibited the SEV- and RIG-I-N-induced activation of IFN-β (Supplementary Fig. S5).
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USP15 affects TGFB1
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USP15 activates TGFB1. 1 / 2
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Three examples of deubiquitinating enzymes for TbetaR-I are ubiquitin specific peptidase-4 (USP4), -11 (USP11) and -15 (USP15), all of which antagonize the effect of SMAD7 and strongly induce TGF-beta1 signalling [XREF_BIBR].
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USP15 affects TAB3
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USP15 activates TAB3. 2 / 2
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For TAB3, USP15 inhibited NBR1 mediated selective autophagic TAB3 degradation independent of its deubiquitinating activity.
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USP15 potentiates NF-kappaB activation by differentially stabilizing TAB2 and TAB3.
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USP15 affects Protease
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USP15 activates Protease. 2 / 2
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To investigate Nef role in protein degradation, we seek to identify cellular proteins involved in the UPS mediated protein degradation through association with Nef and found ubiquitin specific protease 15 (USP15) which stabilizes proteins by deubiquitylation and by preventing autoubiquitylation of substrates.
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To investigate Nef role in protein degradation, we seek to identify cellular proteins involved in the UPS mediated protein degradation through association with Nef and found ubiquitin specific proteas[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP15 affects NFKBIA
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USP15 activates NFKBIA. 2 / 2
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Interestingly, knockdown of both USP15 and USP11 expression leads to an increased basal protein level of IkappaBalpha, suggesting that USP11 and USP15 cooperatively modulate IkappaBalpha turnover.
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An in vitro ubiquitination assay revealed that IkappaBalpha ubiquitination was markedly inhibited by overexpression of CHMP5 or USP15 (XREF_FIG), which is accompanied with pulse-chase labeling experiments showing that IkappaBalpha stability was increased by overexpression of CHMP5 or USP15 (XREF_FIG).
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USP15 affects MEK
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USP15 inhibits MEK. 1 / 2
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In summary, despite markedly reducing BRAP protein levels, USP15 depletion does not promote but rather inhibits MEK activation in response to EGF.
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USP15 affects L-glutamine
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USP15 activates L-glutamine. 2 / 2
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However, changes in expression of Usp15 did not modulate toxicity of a model polyglutamine protein in cell culture.
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Despite increasing aggregation, overexpression of Usp15 did not increase toxicity of the expanded polyglutamine protein.
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USP15 affects Collagen
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USP15 activates Collagen. 2 / 2
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USP15 enhances the proliferation, migration, invasion, and collagen deposition of hypertrophic scar-derived fibroblasts by deubiquitinating TβRI in vitro.
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The authors hypothesized that USP15 was up-regulated and enhanced the proliferation, migration, invasion, and collagen deposition of hypertrophic scar-derived fibroblasts by deubiquitinating TGF-β receptor I (TβRI) in vitro.
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USP15 activates Cicatrix, Hypertrophic. 2 / 2
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USP15 enhances the proliferation, migration, invasion, and collagen deposition of hypertrophic scar-derived fibroblasts by deubiquitinating TβRI in vitro.
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The authors hypothesized that USP15 was up-regulated and enhanced the proliferation, migration, invasion, and collagen deposition of hypertrophic scar-derived fibroblasts by deubiquitinating TGF-β receptor I (TβRI) in vitro.
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USP15 affects Cell Survival
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USP15 activates Cell Survival. 1 / 2
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In conclusion, the results of this study indicate that PRP-Exo-derived USP15 is a key mediator of HaCaT cell survival and migratory activity, with EIF4A1 playing an important role in the process of USP15 induced epithelialization (XREF_FIG).
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USP15 affects CXCL12
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USP15 increases the amount of CXCL12. 2 / 2
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The tumor of the Usp15 -/- chimeric mice had upregulated expression of PD-L1 and CXCL12 (XREF_FIG).
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Excessive IFN-gamma production in USP15 deficient mice promotes expression of the immunosuppressive molecule PD-L1 and the chemokine CXCL12, causing accumulation of T-bet + regulatory T cells and CD11b + Gr-1 + myeloid derived suppressor cells at tumor site.
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USP15 affects CTNNB1
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USP15 inhibits CTNNB1. 2 / 2
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USP4 negatively regulates Wnt signaling by interacting with Nemolike kinase [XREF_BIBR] and USP15 promotes beta-catenin degradation through the stabilization of adenomatous polyposis coli (APC), a negative regulator of Wnt mediated transcription [XREF_BIBR].
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USP15 in turn prevents the basal turnover of beta-catenin by inhibiting its ubiquitin dependent proteasomal degradation, thereby enhancing WNT signaling.
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USP15 affects CDKN1A
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USP15 activates CDKN1A. 2 / 2
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XREF_BIBR, XREF_BIBR Indeed, when U2OS cells were treated with TGF-beta, the levels of USP15 were increased (XREF_FIG), concomitant with an increase in p53 stability and synthesis of p21.
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USP15 knockdown disrupted p53 stability and p21 synthesis mediated by TGF-beta, indicating that TGF-beta modulated p53 stability through upregulation of USP15 synthesis (XREF_FIG).
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USP15 affects CD274
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USP15 increases the amount of CD274. 2 / 2
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The tumor of the Usp15 -/- chimeric mice had upregulated expression of PD-L1 and CXCL12 (XREF_FIG).
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Excessive IFN-gamma production in USP15 deficient mice promotes expression of the immunosuppressive molecule PD-L1 and the chemokine CXCL12, causing accumulation of T-bet + regulatory T cells and CD11b + Gr-1 + myeloid derived suppressor cells at tumor site.
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USP15 affects C6orf89
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USP15 activates C6orf89. 2 / 2
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Endogenous BRAP appears to be constitutively poly- or multiply monoubiquitylated in our system; however, depletion of USP15 promotes the appearance of additional high molecular weight ubiquitylated species of BRAP.
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Our results lead to the prediction that USP15 knockdown may recapitulate the effect of BRAP knockdown by destabilizing and thereby reducing the pool of BRAP that is able to sequester key components of the MAPK module, such as KSR1.
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TRIM25 affects USP15
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TRIM25 activates USP15. 1 / 2
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In cells, the UbVs inhibited the deubiquitination of two USP15 substrates, SMURF2 and TRIM25, and the diUbV inhibited the effects of USP15 on the transforming growth factor beta pathway.
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SMAD6 affects USP15
| 1
SMAD6 inhibits USP15. 1 / 2
| 1
reach
SMAD6 overexpression disrupts the association of USP15 with ALK3 and potently inhibits BMP signalling.
24850914
SART3 affects USP15
| 2
SART3 activates USP15. 2 / 2
| 2
reach
However, the overexpression of SART3 induced the nuclear localization of USP15, consequently leading to colocalization of USP15 with PRP31.
28088760
reach
in which overexpression of SART3 enhanced localization of USP15 to the nucleus.
28088760
RAF1 affects USP15
| 2
RAF1 increases the amount of USP15. 2 / 2
| 2
reach
Instead, our data show a marked decrease of CRAF mRNA levels in USP15 depleted cells, suggesting that USP15 may regulate CRAF transcription.
23105109
reach
However, we were unable to observe an effect of USP15 depletion on luciferase transcription driven from a previously described CRAF-promoter, although we can not fully exclude that USP15 may regulate CRAF transcription via an upstream or downstream element not contained in this 1.2-kb promoter construct.
23105109
MYOD1 affects USP15
2 |
MYOD1 decreases the amount of USP15. 2 / 2
2 |
biopax:msigdb
No evidence text available
biopax:msigdb
No evidence text available
MEIS1 affects USP15
2 |
MEIS1 decreases the amount of USP15. 2 / 2
2 |
biopax:msigdb
No evidence text available
biopax:msigdb
No evidence text available
KEAP1 affects USP15
| 2
KEAP1 inhibits USP15. 2 / 2
| 2
reach
Moreover, depletion of Kelch-like ECH-associated protein 1 (Keap1) diminished the regulatory effect of USP15 inhibition on Nrf2 activation.
34931430
reach
Given that Nrf2 exerts gene regulation in the oxidative stress response, it is quite reasonable that oxidative stress could repress the Keap1 mediated proteasomal degradation of Nrf2 by suppressing US[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
27416755
Interferon affects USP15
| 2
Interferon activates USP15. 2 / 2
| 2
reach
Together, these results suggest that USP15 is not induced by IFN or viral infection, but instead is recruited to TRIM25 upon viral infection.
24399297
reach
In contrast to these host- or virus encoded DUBs that inhibit RIG-I signaling, our study identifies USP15 as a positive regulator of the TRIM25-RIG-I signaling pathway, which is required for a sustained, IFN mediated antiviral response.
24399297
HMBS affects USP15
| 2
HMBS inhibits USP15. 2 / 2
| 2
reach
These data collectively demonstrate that USP15 and Nef could be degraded by the UPS and that these two proteins are involved in regulating degradation of both viral and cellular proteins.Nef is known [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
27460547
reach
These data collectively demonstrate that USP15 and Nef could be degraded by the UPS and that these two proteins are involved in regulating degradation of both viral and cellular proteins.
27460547
GATA1 affects USP15
2 |
GATA1 decreases the amount of USP15. 2 / 2
2 |
biopax:msigdb
No evidence text available
biopax:msigdb
No evidence text available
E6 affects USP15
| 2
E6 activates USP15. 2 / 2
| 2
reach
For example, the non structural protein 1 (NS1) of influenza A virus displaces the SPRY domain by binding to an overlapping contact site on the CC domain [XREF_BIBR], the V proteins of measles, Sendai and parainfluenza viruses bind to the SPRY domain and prevent the interaction of TRIM25 with RIG-I [XREF_BIBR], while the E6 proteins of oncogenic HPVs target TRIM25 and USP15 to promote degradation of the ligase [XREF_BIBR].
31710640
reach
Moreover, the human papillomavirus (HPV) E6 protein increases the activity of USP15 to promote proteasomal degradation of TRIM25, and Herpesvirus mediates autoubiquitination of TRIM25 to prevent K63 linked ubiquitination of RIG-I XREF_BIBR, XREF_BIBR.
31827068
Morphine affects USP15
2 |
Morphine increases the amount of USP15.
1 |
Morphine increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
24068670
Morphine decreases the amount of USP15.
1 |
Morphine decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
24068670
Dioxygen affects USP15
2 |
Dioxygen increases the amount of USP15.
1 |
Dioxygen increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
22629407
Dioxygen decreases the amount of USP15.
1 |
Dioxygen decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
17175027
Bisphenol A affects USP15
2 |
Bisphenol A increases the amount of USP15.
1 |
Bisphenol A increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
28628672
Bisphenol A decreases the amount of USP15.
1 |
Bisphenol A decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
25181051
Benzo[a]pyrene affects USP15
2 |
Benzo[a]pyrene increases the amount of USP15.
1 |
Benzo[a]pyrene increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
15034205
Benzo[a]pyrene decreases the amount of USP15.
1 |
Benzo[a]pyrene decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
17942131
reach
Thus, USP15 knockdown enhanced mitophagy but only in the presence of Parkin.In SH-SY5Y cells, CCCP-induced mitophagy was also markedly promoted by siRNA-mediated knockdown of USP15 ( Fig. 2B and C).
24852371
reach
Thus, USP15 knockdown enhanced mitophagy but only in the presence of Parkin.In SH-SY5Y cells, CCCP-induced mitophagy was also markedly promoted by siRNA-mediated knockdown of USP15 (Fig. 2B and C).
24852371
Acrylamide affects USP15
2 |
Acrylamide increases the amount of USP15.
1 |
Acrylamide increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
28959563
Acrylamide decreases the amount of USP15.
1 |
Acrylamide decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
28959563
USP15 affects superoxide
| 2
USP15 inhibits superoxide.
| 1
USP15 inhibits superoxide. 1 / 1
| 1
reach
Knockout of USP15 significantly reduced intracellular reactive oxygen species (ROS) levels and enhanced superoxide dismutase (SOD) activity in HT22 cells under the exposure to glutamate treatment.
31933062
USP15 activates superoxide.
| 1
USP15 activates superoxide. 1 / 1
| 1
reach
USP15 upregulation was associated with increased levels of intracellular reactive oxygen species (ROS) and enhanced superoxide dismutase (SOD) activity.
33643194
USP15 inhibits homologous recombination. 1 / 1
| 1
reach
We also found that knockdown of 53BP1 in USP15 depleted cells rescued the HR efficiency, as well as PARP inhibitor sensitivity.
30874560
USP15 activates homologous recombination. 1 / 1
| 1
reach
USP15 auto-deubiquitination promotes HR.
30874560
USP15 affects TGFBR1
| 2
USP15 increases the amount of TGFBR1.
| 1
Modified USP15 increases the amount of TGFBR1. 1 / 1
| 1
reach
In contrast, ectopic expression of USP15 did not augment TbetaRI levels or overall TGF-beta luciferase activity in SMURF2 CRSP1 cell lines when expressed alone or in combination with SMURF2 C/A indicating that USP15 's role in the TGF-beta pathway is dependent on SMURF2 function (XREF_SUPPLEMENTARY).
26435193
USP15 activates TGFBR1.
| 1
USP15 activates TGFBR1. 1 / 1
| 1
reach
Moreover, Eichhorn et al. (2012) found that inhibition of USP15 decreased TGF-beta type I receptor and -phosphorylated Smad2 concentrations in these cells, thus corroborating the notion that USP15 sta[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
27155333
USP15 affects TCR
| 2
USP15 bound to MDM2 activates TCR. 1 / 1
| 1
reach
First, USP15 interacts with MDM2, inhibits ubiquitination, and stabilizes MDM2, an important E3 ligase that mediates the ubiquitination and proteolysis of NFATc2 members of the NFAT family and negatively regulates TCR signals.
32850399
USP15 activates TCR. 1 / 1
| 1
reach
found that USP15 was abundantly expressed in immune cells, and the USP15 deficiency promoted the TCR + CD28 - stimulated production of cytokines, such as interleukin 2 (IL-2) and interferon-gamma in naive CD4 + T cells.
28544818
USP15 affects TAB2
| 2
USP15 inhibits TAB2.
| 1
USP15 inhibits TAB2. 1 / 1
| 1
reach
Apart from deubiquitination-dependently inducing cleavage of lysine 48 linked TAB2 ubiquitination, USP15 also DUB-independently inhibited lysosome associated TAB2 degradation, thus enhanced TAB2 stabilization.
31903660
USP15 activates TAB2.
| 1
USP15 activates TAB2. 1 / 1
| 1
reach
USP15 potentiates NF-kappaB activation by differentially stabilizing TAB2 and TAB3.
31903660
USP15 affects SMURF2
| 2
USP15 inhibits SMURF2.
| 1
Modified USP15 inhibits SMURF2. 1 / 1
| 1
reach
Importantly, when we analyzed the ubiquitination pattern of these SMURF2 mutants in lysates of transfected HEK293T cells in the presence of USP15 knockdown vectors, we found that, in addition to wild type SMURF2, loss of USP15 only enhanced SMURF2 ubiquitination in the SMURF2 (K0-734) variant, but not in SMURF2 (K0) " lysine less " mutant (XREF_FIG).
26435193
USP15 decreases the amount of SMURF2.
| 1
USP15 decreases the amount of SMURF2. 1 / 1
| 1
reach
As seen in XREF_SUPPLEMENTARY, USP15 but not USP15 C/S reduced the levels of Ub-SMURF2.
26435193
USP15 affects RLR
| 2
USP15 inhibits RLR.
| 1
USP15 inhibits RLR. 1 / 1
| 1
reach
During human papillomavirus (HPV) infection, the E6 oncoprotein interacts with TRIM25 and ubiquitin-specific peptidase 15 (USP15), which enhances TRIM25 degradation and subsequently inhibits RLR/MAVS signaling.
| PMC
USP15 activates RLR.
| 1
USP15 activates RLR. 1 / 1
| 1
reach
[180] In addition to preventing signaling proteins from degradation by removing K48 linked polyubiquitin chains, USP15 was shown to upregulate RLR signal transduction by indirectly attaching K63 linked polyubiquitin chains on RIG-I.
33511009
USP15 affects RI
| 2
USP15 increases the amount of RI.
| 1
USP15 increases the amount of RI. 1 / 1
| 1
reach
The authors demonstrated that USP15 knockdown significantly inhibited the proliferation, migration, and invasion of hypertrophic scar-derived fibroblasts in vitro and down-regulated the expression of TβRI, Smad2, Smad3, α-SMA, COL1, and COL3; in addition, USP15 overexpression showed the opposite trends (p < 0.05).
34546211
USP15 activates RI.
| 1
USP15 activates RI. 1 / 1
| 1
reach
The authors hypothesized that USP15 was up-regulated and enhanced the proliferation, migration, invasion, and collagen deposition of hypertrophic scar-derived fibroblasts by deubiquitinating TGF-β receptor I (TβRI) in vitro.
34546211
USP15 affects MFN2
| 2
USP15 decreases the amount of MFN2. 1 / 1
| 1
reach
USP15 knockdown enhanced the amount of ubiquitinated endogenous mitofusin-2 in response to mitochondrial depolarization (Fig. 7G and H).
24852371
USP15 decreases the amount of ubiquitinated MFN2. 1 / 1
| 1
reach
We show that USP15 knockdown increases the amount of ubiquitinated mitofusin-2 after mitochondrial depolarization.
24852371
USP15 affects ESR1
| 2
USP15 inhibits ESR1.
| 1
USP15 inhibits ESR1. 1 / 1
| 1
reach
Importantly, USP15 knockdown induced the downregulation of ERalpha protein via promoting its K48 linked ubiquitination, which is required for proliferative inhibition of breast cancer cells.
33771975
USP15 activates ESR1.
| 1
USP15 activates ESR1. 1 / 1
| 1
reach
Specifically, we demonstrated that USP15 promoted the proliferation of ERalpha +, but not ERalpha - breast cancer, in vivo and in vitro.
33771975
USP15 affects EIF4A1
| 1 1
USP15 increases the amount of EIF4A1.
| 1
USP15 increases the amount of EIF4A1. 1 / 1
| 1
reach
Consistent with such a model, we found that USP15 knockdown was sufficient to reduce EIF4A1 expression, while EIF4A1 knockdown directly impaired HaCaT cell migration and proliferation.
| PMC
USP15 activates EIF4A1.
| 1
USP15 activates EIF4A1. 1 / 1
| 1
eidos
These results indicated that USP15 could enhance EIF4A1 expression at the post-transcriptional level .
32671073
USP15 affects BARD1
| 2
USP15 inhibits BARD1.
| 1
USP15 inhibits BARD1. 1 / 1
| 1
reach
Furthermore, ATM inhibitor (Ku55933) treatment also inhibited USP15 mediated BARD1 deubiquitinaion upon DNA damage.
30874560
USP15 activates BARD1.
| 1
USP15 activates BARD1. 1 / 1
| 1
reach
Mechanistically, USP15 promotes BARD1 and BRCA1 retention at DBSs that facilitates DSB end resection.
30874560
USP15 inhibits 3-methylcholanthrene.
| 1
USP15 inhibits 3-methylcholanthrene. 1 / 1
| 1
reach
T cell intrinsic USP15 deficiency promotes excessive IFN-gamma production and an immunosuppressive tumor microenvironment in MCA induced fibrosarcoma.
26686633
USP15 activates 3-methylcholanthrene.
| 1
reach
USP15 deficient T cells promotes MCA induced tumorigenesis.
26686633
USP11 affects USP15
| 2
USP11 deubiquitinates USP15.
| 1
USP11 deubiquitinates USP15. 1 / 1
| 1
reach
UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.
27853171
USP11 activates USP15.
| 1
USP11 activates USP15. 1 / 1
| 1
reach
We also confirmed that USP11 RNAi did not target USP15 and vice versa, confirming that the observed effects of USP11 on the TGFbeta pathway are likely to be due to USP11 (see the electronic supplementary material, figure S4).
22773947
EIF4EBP1 affects USP15
| 2
EIF4EBP1 inhibits USP15.
| 1
EIF4EBP1 inhibits USP15. 1 / 1
| 1
reach
Pre-treatment with LY294002, an inhibitor of PI3K, or with MK2206, an inhibitor of AKT (XREF_SUPPLEMENTARY), or with rapamycin or RAD001 (XREF_SUPPLEMENTARY), the inhibitor of mTOR, blocked the phosphorylation of 4E-BP1 mediated by the PI3K and AKT pathway, and disrupted upregulation of USP15 synthesis mediated by TGF-beta (XREF_FIG).
27893708
EIF4EBP1 activates USP15.
| 1
EIF4EBP1 activates USP15. 1 / 1
| 1
reach
29 Indeed, TGF-beta can increase the phosphorylation of 4E-BP1 and upregulate the synthesis of USP15 (XREF_FIG).
27893708
17alpha-ethynylestradiol increases the amount of USP15.
| 1
17alpha-ethynylestradiol increases the amount of USP15. 1 / 1
| 1
reach
Estrogen deficiency was related to upregulated expression of usp1and usp15, and downregulation of usp2, usp50 and ube2g2, and real time RT-PCR validated these gene expression results, except for usp50.
30930293
17alpha-ethynylestradiol decreases the amount of USP15.
1 |
17alpha-ethynylestradiol decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
23129252
Vinclozolin affects USP15
1 |
Vinclozolin increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
23034163
Tungsten affects USP15
1 |
Tungsten decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
30912803
Tris(1,3-dichloro-2-propyl)phosphate increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
26179874
Trimellitic anhydride increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
19042947
Trichostatin A affects USP15
1 |
Trichostatin A increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
24935251
Topotecan affects USP15
1 |
Topotecan decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
25729387
Phorbol 13-acetate 12-myristate decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
25613284
Perfluorooctane-1-sulfonic acid decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
27153767
Paracetamol affects USP15
1 |
Paracetamol decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
17942131
Oxaliplatin affects USP15
1 |
Oxaliplatin decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
25729387
Nitrosobenzylmethylamine increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
17616710
Mitochondrial DNA damage affects USP15
1 |
Mitochondrial DNA damage decreases the amount of USP15. 1 / 1
1 |
bel
To better understand the consequences of mtDNA deletions, we microarrayed six cell types containing mtDNA deletions from KSS and CPEO patients. Indicated are transcripts shared and downregulated in cells harboring mtDNA deletions in >3 experiments (Table 4); Differentially expressed genes were identified by comparing GeneChips designated as baseline (muscles, myoblasts, fibroblasts, and lymphoblasts from healthy subjects, fusion control cell lines, and parental 143B cells) with the ones that represent the experimental parameters (muscles, myoblasts, fibroblasts, and lymphoblasts from patients, mutant cybrids, and 143B rho zero cells) using a difference in mean fluorescence ? 30 and a P value < 0.05; 37 downregulated genes; 26 upregulated genes;
17157191
Methylmercury compound decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
16966085
Methylmercury chloride increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
23103053
Methyl methanesulfonate increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
23649840
Methotrexate affects USP15
1 |
Methotrexate decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
24449571
Manganese(II) chloride decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
17175027
Manganese atom affects USP15
1 |
Manganese atom decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
17175027
Leflunomide affects USP15
1 |
Leflunomide increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
24136188
Jinfukang affects USP15
1 |
Jinfukang decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
27392435
Ionomycin affects USP15
1 |
Ionomycin decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
25613284
Indometacin affects USP15
1 |
Indometacin increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
28628672
Hypochlorous acid affects USP15
1 |
Hypochlorous acid increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
19376150
Hsa-miR-924 affects USP15
1 |
Hsa-miR-924 decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-7853-5p affects USP15
1 |
Hsa-miR-7853-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-7151-3p affects USP15
1 |
Hsa-miR-7151-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-6838-5p affects USP15
1 |
Hsa-miR-6838-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-6506-5p affects USP15
1 |
Hsa-miR-6506-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-627-5p affects USP15
1 |
Hsa-miR-627-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-619-5p affects USP15
1 |
Hsa-miR-619-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-6078 affects USP15
1 |
Hsa-miR-6078 decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-607 affects USP15
1 |
Hsa-miR-607 decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-5589-5p affects USP15
1 |
Hsa-miR-5589-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-5584-5p affects USP15
1 |
Hsa-miR-5584-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-548e-5p affects USP15
1 |
Hsa-miR-548e-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-548c-3p affects USP15
1 |
Hsa-miR-548c-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-545-3p affects USP15
1 |
Hsa-miR-545-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-541-5p affects USP15
1 |
Hsa-miR-541-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-532-3p affects USP15
1 |
Hsa-miR-532-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-520h affects USP15
1 |
Hsa-miR-520h decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-520g-3p affects USP15
1 |
Hsa-miR-520g-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-520e affects USP15
1 |
Hsa-miR-520e decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-520d-3p affects USP15
1 |
Hsa-miR-520d-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-520c-3p affects USP15
1 |
Hsa-miR-520c-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-520b affects USP15
1 |
Hsa-miR-520b decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-520a-3p affects USP15
1 |
Hsa-miR-520a-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-512-3p affects USP15
1 |
Hsa-miR-512-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-5095 affects USP15
1 |
Hsa-miR-5095 decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-5089-5p affects USP15
1 |
Hsa-miR-5089-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-497-5p affects USP15
1 |
Hsa-miR-497-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-4731-5p affects USP15
1 |
Hsa-miR-4731-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-4713-5p affects USP15
1 |
Hsa-miR-4713-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-4668-5p affects USP15
1 |
Hsa-miR-4668-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-4668-3p affects USP15
1 |
Hsa-miR-4668-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-4438 affects USP15
1 |
Hsa-miR-4438 decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-424-5p affects USP15
1 |
Hsa-miR-424-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-373-3p affects USP15
1 |
Hsa-miR-373-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-372-3p affects USP15
1 |
Hsa-miR-372-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-3671 affects USP15
1 |
Hsa-miR-3671 decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-33a-3p affects USP15
1 |
Hsa-miR-33a-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-3148 affects USP15
1 |
Hsa-miR-3148 decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-302e affects USP15
1 |
Hsa-miR-302e decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-302d-3p affects USP15
1 |
Hsa-miR-302d-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-302c-3p affects USP15
1 |
Hsa-miR-302c-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-302b-3p affects USP15
1 |
Hsa-miR-302b-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-302a-3p affects USP15
1 |
Hsa-miR-302a-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-222-3p affects USP15
1 |
Hsa-miR-222-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23622248
Hsa-miR-2116-3p affects USP15
1 |
Hsa-miR-2116-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-195-5p affects USP15
1 |
Hsa-miR-195-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-186-3p affects USP15
1 |
Hsa-miR-186-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-16-5p affects USP15
1 |
Hsa-miR-16-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-15b-5p affects USP15
1 |
Hsa-miR-15b-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-15a-5p affects USP15
1 |
Hsa-miR-15a-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-150-5p affects USP15
1 |
Hsa-miR-150-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23313552
Hsa-miR-149-5p affects USP15
1 |
Hsa-miR-149-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23622248
Hsa-miR-105-5p affects USP15
1 |
Hsa-miR-105-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-miR-103a-3p affects USP15
1 |
Hsa-miR-103a-3p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
20371350
Hsa-let-7b-5p affects USP15
1 |
Hsa-let-7b-5p decreases the amount of USP15. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
18668040
Gold atom affects USP15
1 |
Gold atom decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
25523186
Fumonisin B1 affects USP15
1 |
Fumonisin B1 decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
16221962
Formaldehyde affects USP15
1 |
Formaldehyde increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
23649840
Folic acid affects USP15
1 |
Folic acid decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
20938992
Flutamide affects USP15
1 |
Flutamide increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
24136188
Ethyl methanesulfonate increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
23649840
Enzyme inhibitor affects USP15
1 |
ctd
No evidence text available
23301498
Endocrine disruptor increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
25198161
Dorsomorphin affects USP15
1 |
Dorsomorphin increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
27188386
Dicrotophos affects USP15
1 |
Dicrotophos decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
28302478
Dexamethasone affects USP15
1 |
Dexamethasone increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
28628672
Deoxynivalenol affects USP15
1 |
Deoxynivalenol increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
22846391
Cyclosporin A affects USP15
1 |
Cyclosporin A decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
17942131
Cupric oxide affects USP15
1 |
Cupric oxide increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
22077320
Choline affects USP15
1 |
Choline decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
20938992
Calcium atom affects USP15
1 |
Calcium atom increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
24068670
Cadmium dichloride increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
24527689
Butanal affects USP15
1 |
Butanal decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
26079696
Bisphenol F affects USP15
1 |
Bisphenol F increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
28628672
Bis(tri-n-butyltin)oxide decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
17942131
Beta-endorphin affects USP15
1 |
Beta-endorphin increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
24068670
Acetylsalicylic acid increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
11906190
Acetohydrazide affects USP15
1 |
Acetohydrazide decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
15282401
Abrine affects USP15
1 |
Abrine increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
31054353
ZEB1 affects USP15
1 |
ZEB1 decreases the amount of USP15. 1 / 1
1 |
biopax:msigdb
No evidence text available
Water Pollutants, Chemical increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
25198161
Usp32 affects USP15
| 1
Usp32 inhibits USP15. 1 / 1
| 1
reach
If CG8334 inhibits mitophagy in flies, similar to USP15 in human cells, suppression of CG8334 levels would allow residual Parkin in parkin RNAi flies to target damaged mitochondria for removal.Parkin regulates mitochondrial homeostasis also through pathways unrelated to MOM protein ubiquitination and mitophagy.
24852371
USP15 affects wound healing
| 1
USP15 activates wound healing. 1 / 1
| 1
eidos
Our group previously demonstrated that USP15 could directly accelerate wound healing by stabilizing TBR1 and maintaining the TGF-beta signaling pathway in fibroblasts ( Zhao et al ., 2019 ) .
32671073
USP15 affects viral life cycle
| 1
eidos
In addition , the ectopic expression of USP15 enhances the TRIM25 - and RIG-I-mediated production of type I IFN and thus suppresses RNA virus replication , whereas the depletion of USP15 causes decreased IFN production and markedly enhanced viral replication ( 85 ) .
34707613
USP15 affects translocation
| 1
eidos
We also investigated whether USP15 inhibited the translocation of Parkin from the cytosol to depolarized mitochondria .
24852371
USP15 affects translation
| 1
USP15 activates translation. 1 / 1
| 1
reach
A recent study by Matsuura and group noted that USP15 augments HCV mRNA translation and thus viral propagation.
31481479
reach
Overexpression of USP15 potentiated TNFalpha- or IL-1beta-triggered NF-kappaB activation and downstream genes transcription, whereas knockdown of USP15 had opposite effects.
31903660
USP15 affects tamoxifen
| 1
USP15 inhibits tamoxifen. 1 / 1
| 1
reach
Meanwhile, USP15 knockdown notably enhanced the antitumor activities of tamoxifen on breast cancer cells.
33771975
USP15 affects runx1
| 1
USP15 activates runx1. 1 / 1
| 1
reach
A preclinical small-molecule inhibitor of USP15 induced the KEAP1-NRF2 axis and impaired AML cell function, suggesting that targeting USP15 catalytic function can suppress AML.
34465865
eidos
The sfRNA from an epidemic strain of DENV interacts with TRIM25 and impedes its deubiquitination and stabilization by USP15 , a cellular DUB .
33530371
reach
Ubiquitination of Prp31 increases its affinity for Prp8 and this PTM is reversed by USP15.
| PMC
USP15 affects nuclear export
| 1
USP15 inhibits nuclear export. 1 / 1
| 1
eidos
USP15 inhibits the nuclear export , ubiquitination , and lysosome-mediated degradation of R175H mutp53 independently of MDM2 in ovarian cancer cells ( Padmanabhan et al ., 2018 ) .
32722796
USP15 affects morphine(1+)
| 1
USP15 inhibits morphine(1+). 1 / 1
| 1
reach
Additionally, USP15 silencing also abolished the inhibitory effect of morphine on NF-kappaB signaling 14.
30459344
USP15 affects hexadecane
| 1
USP15 activates hexadecane. 1 / 1
| 1
reach
Thus, future studies using conditional deletion of USP15 will address how USP15 signaling in CNS resident cells and peripheral immune cells contribute to neuroinflammation.
27984564
USP15 affects fbxw1
| 1
USP15 inhibits fbxw1. 1 / 1
| 1
reach
Therefore, USP15 does not antagonize betaTrCP at mitosis.
23708518
USP15 bound to TRIM25 activates defense response to virus. 1 / 1
| 1
reach
USP15 binds to TRIM25 in viral infections, detaching the K48-linked ubiquitin chains assembled by LUBAC on TRIM25, thereby stabilizing the TRIM25 protein levels and promoting a sustained antiviral response (Figure 3).
29018447
USP15 inhibits cytokine production. 1 / 1
| 1
reach
Thus, USP15 negatively regulates T cell cytokine production via its DUB function.
24777531
USP15 affects cell death
| 1
USP15 activates cell death. 1 / 1
| 1
reach
Depletion of USP15 in ovarian cancer cells causes decrease in p53-R175H protein levels and induces cell death in cancer cells expressing this mutant form of p53 [XREF_BIBR].
29854875
USP15 affects autophagy
| 1
USP15 inhibits autophagy. 1 / 1
| 1
reach
miR-26a also modifies the activity of the downstream target Usp15, which can inhibit mitochondrial autophagy by activating the PINK1 and PRKN pathway.
33884101
reach
USP15 knockdown inhibits alkaline phosphatase activity.
24850914
USP15 affects Ubiquitination
| 1
eidos
USP15 inhibits the nuclear export , ubiquitination , and lysosome-mediated degradation of R175H mutp53 independently of MDM2 in ovarian cancer cells ( Padmanabhan et al ., 2018 ) .
32722796
USP15 affects UBE2C
| 1
USP15 activates UBE2C. 1 / 1
| 1
reach
Of the 4 DUBs able to rescue substrate degradation, only USP15 was able to fully restore Ube2C charging.
33417828
USP15 affects TUMOR-IMMUNITY
| 1
USP15 inhibits TUMOR-IMMUNITY. 1 / 1
| 1
trips
USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2.
32948596
USP15 affects TILs
| 1
USP15 inhibits TILs. 1 / 1
| 1
reach
Deletion of Usp15 in melanoma stimulates chemokine expression and TILs in a TET2 dependent manner, leading to increased response to immunotherapy and extended life span of tumor bearing mice.
32948596
USP15 affects SQSTM1
| 1
USP15 inhibits SQSTM1. 1 / 1
| 1
reach
Indeed, overexpression of wild-type USP15 dramatically decreased short-chain modification of SQSTM1 with ubiquitin in a manner dependent on its catalytic Cys 269 residue (XREF_FIG A and 6B).
27368102
USP15 affects SP1
| 1
USP15 activates SP1. 1 / 1
| 1
reach
As shown in XREF_FIG, co-expression of USP15 enhanced the AP-1, AP-2, AP-3, SP-1 and NF-kappaB signal pathways transactivated by ectopically expressed HBx although these signal pathways were also affected to a lesser extent by USP15 overexpression alone (XREF_FIG).
28074857
USP15 affects SMAD3
| 1
USP15 increases the amount of SMAD3. 1 / 1
| 1
reach
The authors demonstrated that USP15 knockdown significantly inhibited the proliferation, migration, and invasion of hypertrophic scar-derived fibroblasts in vitro and down-regulated the expression of TβRI, Smad2, Smad3, α-SMA, COL1, and COL3; in addition, USP15 overexpression showed the opposite trends (p < 0.05).
34546211
USP15 affects RNF26
| 1
USP15 inhibits RNF26. 1 / 1
| 1
reach
Furthermore, expression of wild-type (but not inactive) USP15 reduced the degree of colocalization of RNF26 with SQSTM1 (XREF_FIG C, 6D, and XREF_FIG B), indicating that USP15 activity modulates occupancy of ligase positive sites.
27368102
USP15 activates RIG-I signaling pathway. 1 / 1
| 1
eidos
To sum up , USP15 is a novel modulator of RIG-I signaling pathway .
26061460
USP15 affects Podocytes
| 1
USP15 inhibits Podocytes. 1 / 1
| 1
eidos
Further investigation showed that inhibition of USP15 enhanced the activation of NF-E2-related factor 2 ( Nrf2 ) and expression of Nrf2 target genes in HG-simulated podocytes .
34931430
USP15 affects PPIP5K1
| 1
USP15 inhibits PPIP5K1. 1 / 1
| 1
reach
Interestingly, USP15 competes with IPS-1 to bind to RIG-1, limiting IPS-1 activation and IFN1 production.
33138315
USP15 affects PINK1
| 1
USP15 activates mutated PINK1. 1 / 1
| 1
reach
Furthermore, USP15 KD was able to rescue the mitophagy defect of Parkin and PINK1 mutant PD patient fibroblasts.
26550693
USP15 affects PI3K
| 1
USP15 inhibits PI3K. 1 / 1
| 1
reach
USP15 promotes the apoptosis of degenerative nucleus pulposus cells by suppressing the PI3K and AKT signalling pathway.
33135363
USP15 affects Oxidative Stress
| 1
USP15 inhibits Oxidative Stress. 1 / 1
| 1
eidos
Inhibition of USP15 led to decreases in HG-evoked apoptosis , oxidative stress , and inflammation in podocytes .
34931430
eidos
Recently , USP15 inhibition was found to prevent glutamate-induced oxidative damage and neurotoxicity by activating the Nrf2 / HO-1 signaling pathway in HT22 cells [ 96 ] , suggesting that USP15 might be a promising therapeutic target to prevent disease progression associated with Nrf2 activation .
33946990
USP15 affects NOP53
| 1
USP15 activates NOP53. 1 / 1
| 1
reach
USP15 mediated GLTSCR2 removal of RIG-I ubiquitination.
27824081
USP15 affects NFKB1
| 1
USP15 inhibits NFKB1. 1 / 1
| 1
reach
Three human DUBs, CYLD, A20 and DUBA, have been shown to negatively regulate the innate immune response by removing K63-based chains [55, 56] , and USP15 inhibits the NFkB pathway by removing K48-Ub from IkBa, preventing its degradation [57] .
24854014
USP15 affects NFASC
| 1
USP15 inhibits NFASC. 1 / 1
| 1
reach
Three human DUBs, CYLD, A20 and DUBA, have been shown to negatively regulate the innate immune response by removing K63-based chains [55], [56], and USP15 inhibits the NFκB pathway by removing K48-Ub from IκBα, preventing its degradation [57].
24854014
USP15 affects NELFCD
| 1
USP15 activates NELFCD. 1 / 1
| 1
reach
USP15 deficiency promotes Th1 responses against bacterial infections and tumor challenge in a transplantable melanoma model 231.
27012466
USP15 affects NBR1
| 1
USP15 activates NBR1. 1 / 1
| 1
reach
For TAB3, USP15 inhibited NBR1 mediated selective autophagic TAB3 degradation independent of its deubiquitinating activity.
31903660
USP15 affects MXD1
| 1
USP15 activates MXD1. 1 / 1
| 1
reach
USP15 has recently been shown to deubiquitylate and thereby activate R-SMAD (Sma and Mad Related Family) transcription factors.
23105109
USP15 affects MDM4
| 1
USP15 activates MDM4. 1 / 1
| 1
reach
Whether USP15 also modulates MDMX stability, how the activity of USP15 is regulated, and whether DNA damage impacts USP15 activity toward MDM2 remain to be elucidated.
25808808
USP15 affects MAPRE1
| 1
USP15 inhibits MAPRE1. 1 / 1
| 1
reach
As demonstrated in Figure 5 (a) and (b), USP15 over-expression accelerated EB1 degradation significantly in control cells and to a smaller extent in siCSN1 cells.
17350042
USP15 affects KDM1A
| 1
USP15 increases the amount of KDM1A. 1 / 1
| 1
reach
We therefore screened a panel of DUBs in which 23 DUBs ' cDNA plasmids were transfected into 293T cells, and found that USP15, USP21, USP22, and USP28 upregulated KDM1A levels (XREF_SUPPLEMENTARY).
27501329
USP15 affects IL6
| 1
USP15 activates IL6. 1 / 1
| 1
reach
Importantly, Hrd1 deficiency in macrophages protects mice against lipopolysaccharide induced septic shock, and knockdown of Usp15 in Hrd1-knockout macrophages restores the reduced IL-6 production.
31477895
USP15 affects HUWE1
| 1
USP15 inhibits HUWE1. 1 / 1
| 1
reach
Conversely, whereas USP4 and USP15 target p53 inhibiting ligases ARF-BP1 [XREF_BIBR] and MDM2 [XREF_BIBR], respectively, USP11 stabilizes p53 [XREF_BIBR] as well as several other tumor suppressors including PML [XREF_BIBR], BRCA2 [XREF_BIBR] and Mre11 complex members MRE11 & RAD50 [XREF_BIBR].
26503449
USP15 affects HMOX1
| 1
USP15 decreases the amount of HMOX1. 1 / 1
| 1
reach
Myc-USP15 was shown to decrease endogenous Nrf2, NQO1, and HO-1 protein levels when compared to control, with no change in Keap1 (XREF_FIG).
23727018
USP15 affects HMOX
| 1
USP15 decreases the amount of HMOX. 1 / 1
| 1
reach
Furthermore, USP15 inhibition induced nuclear factor erythroid derived 2 related factor2 (Nrf2) nuclear translocation and promoted protein expression level of heme oxygenase (HO-1).
31933062
USP15 affects HECTD1
| 1
USP15 decreases the amount of HECTD1. 1 / 1
| 1
reach
We have demonstrated that downregulation of USP15 in GBM cells reduced HECTD1 levels, and that HECTD1 was substrate for de-ubiquinitation by USP15, but not by its functional mutant, suggesting that USP15 stabilizes HECTD1.
29299163
USP15 affects ERK
| 1
USP15 increases the amount of phosphorylated ERK. 1 / 1
| 1
reach
Interestingly, USP15 did not regulate the stability of ERK2 but increased the level of p-ERK1/2 to further enhance the TGF-beta and SMAD2 signaling pathway.
33726807
USP15 affects E3_Ub_ligase
| 1
USP15 activates E3_Ub_ligase. 1 / 1
| 1
reach
The fact that USP15 simultaneously targets both the E3 ligase and its respective substrate, TGF-beta receptor, is unsurprising.
26435193
USP15 affects Death
| 1
USP15 inhibits Death. 1 / 1
| 1
reach
Silencing USP15 protected against glutamate mediated neuronal cell death, and inhibited the high expression levels of cleaved caspase-3.
31933062
USP15 affects Dclk3
| 1
USP15 inhibits Dclk3. 1 / 1
| 1
reach
Furthermore, USP15 knockdown and knockout specifically enhance CARD9 dependent CLR signaling in both mouse and human immune cells.
33093067
USP15 affects DNA repair
| 1
USP15 activates DNA repair. 1 / 1
| 1
reach
Next, we examined how USP15 promotes DNA repair using integrated reporter assays for HR and NHEJ 56.
30874560
USP15 affects DNA Damage
| 1
USP15 activates DNA Damage. 1 / 1
| 1
reach
Whether USP15 also modulates MDMX stability, how the activity of USP15 is regulated, and whether DNA damage impacts USP15 activity toward MDM2 remain to be elucidated.
25808808
USP15 affects DEK
| 1
USP15 activates DEK. 1 / 1
| 1
reach
USP15 overexpression enhanced DEK stability, the effect of which was impaired by KIF15 knockdown.
34280614
USP15 affects Cartilage
| 1
USP15 activates Cartilage. 1 / 1
| 1
eidos
Our results indicated that USP15 stimulated TGF-beta / SMAD2 signaling and the cartilage phenotype .
33726807
USP15 affects COL3
| 1
USP15 increases the amount of COL3. 1 / 1
| 1
reach
The authors demonstrated that USP15 knockdown significantly inhibited the proliferation, migration, and invasion of hypertrophic scar-derived fibroblasts in vitro and down-regulated the expression of TβRI, Smad2, Smad3, α-SMA, COL1, and COL3; in addition, USP15 overexpression showed the opposite trends (p < 0.05).
34546211
USP15 affects COL1
| 1
USP15 increases the amount of COL1. 1 / 1
| 1
reach
The authors demonstrated that USP15 knockdown significantly inhibited the proliferation, migration, and invasion of hypertrophic scar-derived fibroblasts in vitro and down-regulated the expression of TβRI, Smad2, Smad3, α-SMA, COL1, and COL3; in addition, USP15 overexpression showed the opposite trends (p < 0.05).
34546211
USP15 affects CENPA
| 1
USP15 activates CENPA. 1 / 1
| 1
reach
USP15 depletion leads to centromere protein A (CENP-A)-positive micronuclei.
29429988
USP15 affects CD8
| 1
USP15 activates CD8. 1 / 1
| 1
reach
Although USP15 does not have a cell-intrinsic role in regulating CD8 + T cells, the USP15 deficiency also promotes CD8 + T cell responses in vivo, likely due to stronger helper function of Th1 cells.
26686633
USP15 affects CD28
| 1
USP15 activates CD28. 1 / 1
| 1
reach
found that USP15 was abundantly expressed in immune cells, and the USP15 deficiency promoted the TCR + CD28 - stimulated production of cytokines, such as interleukin 2 (IL-2) and interferon-gamma in naive CD4 + T cells.
28544818
USP15 affects CCCP
| 1
USP15 inhibits CCCP. 1 / 1
| 1
reach
More in detail, USP15 was shown to inhibit CCCP induced mitophagy in Parkin transfected Hela cells depending on its DUB activity and RNAi mediated silencing of USP15 enhanced Parkin mediated mitophagy[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
26550693
USP15 affects BRCA1
| 1
USP15 activates BRCA1. 1 / 1
| 1
reach
Mechanistically, USP15 promotes BARD1 and BRCA1 retention at DBSs that facilitates DSB end resection.
30874560
USP15 affects BIRC5
| 1
Modified USP15 increases the amount of BIRC5. 1 / 1
| 1
reach
USP15 overexpression promotes the expression of Bcl-2, Bcl-xL, Survivin, and NF-kappaBp65.
30459344
USP15 affects BCL2L1
| 1
Modified USP15 increases the amount of BCL2L1. 1 / 1
| 1
reach
USP15 overexpression promotes the expression of Bcl-2, Bcl-xL, Survivin, and NF-kappaBp65.
30459344
USP15 affects BCL2
| 1
Modified USP15 increases the amount of BCL2. 1 / 1
| 1
reach
USP15 overexpression promotes the expression of Bcl-2, Bcl-xL, Survivin, and NF-kappaBp65.
30459344
USP15 activates Adaptor_protein_III. 1 / 1
| 1
reach
As shown in XREF_FIG, co-expression of USP15 enhanced the AP-1, AP-2, AP-3, SP-1 and NF-kappaB signal pathways transactivated by ectopically expressed HBx although these signal pathways were also affected to a lesser extent by USP15 overexpression alone (XREF_FIG).
28074857
reach
As shown in XREF_FIG, co-expression of USP15 enhanced the AP-1, AP-2, AP-3, SP-1 and NF-kappaB signal pathways transactivated by ectopically expressed HBx although these signal pathways were also affected to a lesser extent by USP15 overexpression alone (XREF_FIG).
28074857
USP15 affects AP1
| 1
USP15 activates AP1. 1 / 1
| 1
reach
As shown in XREF_FIG, co-expression of USP15 enhanced the AP-1, AP-2, AP-3, SP-1 and NF-kappaB signal pathways transactivated by ectopically expressed HBx although these signal pathways were also affected to a lesser extent by USP15 overexpression alone (XREF_FIG).
28074857
USP15 affects AKT
| 1
USP15 inhibits AKT. 1 / 1
| 1
reach
USP15 promotes the apoptosis of degenerative nucleus pulposus cells by suppressing the PI3K and AKT signalling pathway.
33135363
TP53 affects USP15
| 1
TP53 activates USP15. 1 / 1
| 1
reach
Conversely, whereas USP4 and USP15 target p53 inhibiting ligases ARF-BP1 [XREF_BIBR] and MDM2 [XREF_BIBR], respectively, USP11 stabilizes p53 [XREF_BIBR] as well as several other tumor suppressors including PML [XREF_BIBR], BRCA2 [XREF_BIBR] and Mre11 complex members MRE11 & RAD50 [XREF_BIBR].
26503449
TNFSF11 affects USP15
| 1
TNFSF11 increases the amount of USP15. 1 / 1
| 1
reach
Intriguingly, CHMP5 and USP15 expression are both up-regulated by RANKL, suggesting that they may function in concert as a negative feedback mechanism to suppress NF-kappaB activity (XREF_FIG).
26195726
TIFAB affects USP15
| 1
TIFAB activates USP15. 1 / 1
| 1
eidos
Importantly , when TIFAB was incubated with another USP enzyme , USP7 , we could not detect a discernable increase in the rate of ubiquitin hydrolysis with TIFAB , indicating that the effects of TIFAB are , at least , partly selective to USP15 ( Figure S1E ) .
32101751
TCF3 affects USP15
1 |
TCF3 decreases the amount of USP15. 1 / 1
1 |
biopax:msigdb
No evidence text available
SP1 affects USP15
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SP1 decreases the amount of USP15. 1 / 1
1 |
biopax:msigdb
No evidence text available
Radiation, Ionizing activates USP15. 1 / 1
| 1
reach
IR induced USP15 translocation to the nucleus.
30874560
PRNP affects USP15
| 1
PRNP activates USP15. 1 / 1
| 1
reach
To understand the functional effects of USP15 on HaCaT cells, they were next treated with PBS, PRP, and PRP-Exos.
| PMC
PRKN affects USP15
| 1
PRKN activates USP15. 1 / 1
| 1
reach
Whilst the phosphatase that dephosphorylates p-Ub remains unknown, two DUBs have been identified that deubiquitylate Parkin directed substrates, USP30 and USP15, and USP8 has also been reported to reverse Parkin autoubiquitylation.
28408429
PRH2 affects USP15
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PRH2 activates USP15. 1 / 1
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reach
Treatment of cells with probe 1 led to labeling of USP15 and USP7, but not by HA-Ub-PA (XREF_SUPPLEMENTARY).
30240200
PI3K affects USP15
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PI3K activates USP15. 1 / 1
| 1
reach
Taken together, our results demonstrate that TGF-beta signaling can regulate p53 stability through upregulation of USP15 translation mediated by the PI3K and AKT pathway and partly elucidate why TGF-beta can suppress cancer progression in early stages when cells express wild-type p53.
27893708
NFE2L1 affects USP15
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NFE2L1 activates USP15. 1 / 1
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reach
Furthermore, the overexpression of Nrf1 markedly promotes the nuclear translocation of USP15, similar to the case of the nuclear protein Tip110 [24].
27416755
NFATC2 affects USP15
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NFATC2 activates USP15. 1 / 1
| 1
reach
In contrast, HLI373 did not appreciably enhance NFATc2 activation or cytokine induction in Usp15 -/- T cells (XREF_SUPPLEMENTARY), further suggesting that the USP15 deficiency causes T cell hyperactivation via downregulation of MDM2 (XREF_FIG).
24777531
Multiple Myeloma affects USP15
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Multiple Myeloma inhibits USP15. 1 / 1
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sparser
PDTC treatment inhibits USP15 overexpression-induced MM cell proliferation and apoptosis inhibition.
30459344
MCB-613 affects USP15
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MCB-613 activates USP15. 1 / 1
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reach
Interestingly, MCB-613 treatment resulted in decreased USP15 protein levels in TYK-Nu (R175H) and OVCA420 (R273H) cells, suggesting that MCB-613 causes depletion of USP15 protein through a post-translational mechanism.
29593334
L-methionine affects USP15
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L-methionine decreases the amount of USP15. 1 / 1
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ctd
No evidence text available
20938992
IL1R2 affects USP15
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IL1R2 inhibits USP15. 1 / 1
| 1
reach
IL1R2 Blockade Suppresses Breast Tumorigenesis and Progression by Impairing USP15 Dependent BMI1 Stability.
31921558
IFNG affects USP15
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IFNG activates USP15. 1 / 1
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reach
T cells are major source of aberrant IFN-gamma production in Usp15 -/- mice.
26686633
Flavonoids affects USP15
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Flavonoids increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
18035473
EGR3 affects USP15
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EGR3 decreases the amount of USP15. 1 / 1
1 |
biopax:msigdb
No evidence text available
EGR2 affects USP15
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EGR2 decreases the amount of USP15. 1 / 1
1 |
biopax:msigdb
No evidence text available
EGR1 affects USP15
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EGR1 decreases the amount of USP15. 1 / 1
1 |
biopax:msigdb
No evidence text available
DDX58 affects USP15
| 1
DDX58 bound to NOP53 activates USP15. 1 / 1
| 1
reach
These results taken together indicated that GLTSCR2 interacted with RIG-I and USP15 in a complex to support the activity of USP15 to remove K63 linked polyubiquitin chains from RIG-I, leading to inactivation of RIG-I and blockage of IFN-beta induction.
27824081
CXCL12 affects USP15
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CXCL12 activates USP15. 1 / 1
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reach
These data suggest that aberrant production of the chemokine CXCL12 contributes to the accumulation of tumor infiltrating MDSCs in the Usp15 -/- mice.
26686633
CTAP octapeptide affects USP15
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CTAP octapeptide increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
24068670
CD274 affects USP15
| 1
CD274 inhibits USP15. 1 / 1
| 1
reach
The PD-L1 antibody significantly reduced the incidence of MCA induced tumors in both wildtype and Usp15 -/- mice (XREF_FIG and XREF_SUPPLEMENTARY).
26686633
C6orf89 affects USP15
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C6orf89 activates USP15. 1 / 1
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reach
What then is the relevant BRAP independent target of USP15?
23105109
BMPR1A affects USP15
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BMPR1A activates USP15. 1 / 1
| 1
reach
USP15 targets ALK3 and BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling.
24850914
BARD1 affects USP15
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BARD1 activates USP15. 1 / 1
| 1
reach
Since USP15 interacts with BARD1 and this interaction is important for HR, we hypothesized that BARD1 is the prime target of USP15.
30874560
Antirheumatic Agents decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
24449571
AKT affects USP15
| 1
AKT activates USP15. 1 / 1
| 1
reach
Taken together, our results demonstrate that TGF-beta signaling can regulate p53 stability through upregulation of USP15 translation mediated by the PI3K and AKT pathway and partly elucidate why TGF-beta can suppress cancer progression in early stages when cells express wild-type p53.
27893708
4-hydroxyphenyl retinamide decreases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
28973697
3-isobutyl-1-methyl-7H-xanthine increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
28628672
2,3,7,8-tetrachlorodibenzodioxine increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
15034205
1-nitropyrene affects USP15
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1-nitropyrene increases the amount of USP15. 1 / 1
1 |
ctd
No evidence text available
19041380