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
152 retrieved on 2022-05-22

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

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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.
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.
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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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.
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.
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
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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.

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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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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.
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.
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.
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).
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.
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.
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.
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.

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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.

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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.
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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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.
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]
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).
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.
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.
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.
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]
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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).
USP15 deubiquitinates KEAP1 on lysine. 1 / 1
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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).
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
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.
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]
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.
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.
USP15 deubiquitinates RBX1. 1 / 1
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Review
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.
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.
Modified USP15 leads to the deubiquitination of RELA. 1 / 1
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Additionally, USP15 overexpression significantly inhibited the ubiquitination of NF-kappaBp65.
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.
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.
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.
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.
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.
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.
USP15 deubiquitinates RI. 1 / 1
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Co-immunoprecipitation and ubiquitination assays revealed that USP15 interacted with TβRI and deubiquitinated TβRI.
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.
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.
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.
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.
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.
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 lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan 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.
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).
USP15 inhibits TGFB.
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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.
USP15 affects IFNB1
| 27
USP15 inhibits IFNB1.
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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.
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.
USP15 decreases the amount of IFNB1.
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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).
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.
USP15 activates IFNB1.
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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.
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).
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.
USP15 activates REST.
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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).
USP15 increases the amount of REST.
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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 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 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.
USP15 affects TRIM25
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USP15 activates TRIM25.
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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).
USP15 inhibits TRIM25.
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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.
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USP15 increases the amount of TRIM25.
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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.
USP15 affects Interferon
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USP15 inhibits Interferon.
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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.
USP15 activates Interferon.
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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 ) .
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.
TGFB affects USP15
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TGFB activates USP15.
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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.
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).
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.
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).
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.
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).
USP15-C269S activates TP53. 2 / 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).
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).
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].
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).
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).
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]
USP15 affects NFkappaB
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USP15 activates NFkappaB.
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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).
USP15 inhibits NFkappaB.
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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 ) .
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.
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].
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.
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.
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.
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.
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.