USP4 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 4
HGNC Gene Symbol
USP4
Identifiers
hgnc:12627 NCBIGene:7375 uniprot:Q13107
Orthologs
mgi:98905 rgd:1587387
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP4
Number of Papers
172 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
GLT8D1 glycosyltransferase 8 domain containing 1 0.26 0.02 -0.00 8.44e-01
PPM1M protein phosphatase, Mg2+/Mn2+ dependent 1M 0.252
TMEM42 transmembrane protein 42 0.226
CCKAR cholecystokinin A receptor 0.221 Reactome (1)
BBS10 Bardet-Biedl syndrome 10 0.214
KLRK1 killer cell lectin like receptor K1 0.21
CYP8B1 cytochrome P450 family 8 subfamily B member 1 0.209

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP4using 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

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out USP4 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
MT-ND2 mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 2 2.93e-01 1.93e-06 4.26e-02

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 USP4 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
USP4 deubiquitinates MAP3K7. 10 / 13
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USP4 deubiquitinates TAK1 in vitro and in vivo.
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These results indicate that USP4 mainly inhibits inducible TAK1 polyubiquitination and activation whereas CYLD mainly inhibits basal level of TAK1 polyubiquitination and activation.
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USP4 deubiquitinates TAK1 in vivo and in vitro.
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Using a functional genomic approach, we have identified ubiquitin-specific peptidase 4 (USP4) as a deubiquitinase for TAK1.
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In addition, USP4 inhibits TNF-alpha-induced activation of NF-kappaB through USP4 deubiquitination of TAK1 XREF_BIBR.
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Although it has been reported that USP4 deubiquitinates TAK1 and negatively regulates TNF- and IL-1-induced activation of NF-kappaB, how TAK1 ubiquitination is regulated in adaptive immune cells such as T cells and whether such a regulation regulates T cell mediated immune response remain unknown.
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USP4 also deubiquitinates TAK1 in HEK293 T cells [62].
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In view of the data presented here and previous reports, we propose a working model (XREF_FIG), in which that TNFalpha rapidly induces Lys63 linked TAK1 polyubiquitnation and binding of USP4 to TAK1, Lys63 linked TAK1 would be rapidly deubiquitinated by USP4 to attenuate the magnitude of TNFalpha induced Lys63 linked TAK1 polyubiquitination and TAK1 mediated IKK and NF-kappaB activation.
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We then analyzed the effect of USP4 knockdown on the TNFalpha induced TAK1 polyubiquitination.
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In conclusion, our results provide evidence that TNFalpha induces association of USP4 with TAK1 which leads to TAK1 deubiquitination in the TNFalpha mediated NF-kappaB activation.
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USP4 deubiquitinates PRPF3. 10 / 11
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In particular, non proteolytic ubiquitylation of the U4/U6 protein Prp3, promoted by the Prp19 complex, is required for stabilization of the U4/U6 * U5 tri-snRNP, while de-ubiquitylation of Prp3 by Usp4 and Sart3 is required for U4 dissociation and recycling.
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On the other hand, Usp4 and Sart3 promote de-ubiquitination and recycling of Prp3, and this modification weakens its interaction with Prp8 and allows for the dissociation of U4 during activation of the spliceosome [49].
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Moreover, we found that USP15 and USP4 deubiquitinated substrates PRP31 and PRP3 simultaneously.
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U5 tri-snRNP has joined the spliceosome, Usp4 deubiquitinates Prp3, decreasing its affinity for Prp8.
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Prp3 is deubiquitinated by Usp4, and is therefore unlikely to be a target for Bre5-Ubp3.
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Prp3 is deubiquitinated by Usp4 and its substrate targeting factor, the U4/U6 recycling protein Sart3, which likely facilitates ejection of U4 proteins from the spliceosome during maturation of its active site.
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USP15SART3 makes a complex with USP4 and this ternary complex serves as a platform to deubiquitinate PRP31 and PRP3
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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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PRP3 was deubiquitinated by USP4 consistent with a previous report but not by USP15.
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The result shows that USP4 no longer deubiquitinates Prp3 in the presence of SART3 DeltaNLS.
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USP4 deubiquitinates TGFBR1. 10 / 11
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USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor [XREF_BIBR].
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This phosphorylation promotes USP4 localization in membrane and cytoplasm, where USP4 deubiquitylates TbetaRI.
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For instance, USP4 directly interacts with and deubiquitinates TGF-beta type I receptor (TbetaRI), thereby determining the levels of TGF-beta signaling.
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Mechanistically, we revealed that USP4 interacted directly with and deubiquitinated TGF-beta receptor type I (TGFR-1) to activate the TGF-beta signaling pathway, and subsequently induced the Epithelial-Mesenchymal Transition (EMT) in HCC cells.
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USP4 can also deubiquitinate TGF-beta type I receptor (TbetaRI) and sustain its plasma membrane expression in a SMAD7 independent fashion, leading to hyperactivation of the TGF-beta pathway.
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USP4 is a DUB for TGF-β type I receptor
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USP4 is regulated by AKT phos phorylation and directly deubiquitylates TGF-beta type I receptor.
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As mentioned above, USP4 binds to and deubiquitinates the TGF-beta type I receptor and associates with AKT, leading to enhanced TGF-beta signalling and AKT induced breast cancer cell migration (Zhang [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor.
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Taken together, our results elucidate that USP4 is highly expressed in HCC and promotes the tumor invasion and metastasis, the underlying mechanism is that USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-beta signaling Induced EMT.
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USP4 deubiquitinates HUWE1. 10 / 10
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USP2 deubiquitinates both MDM2 and MDMX [XREF_BIBR, XREF_BIBR] whereas USP4 deubiquitinates ARF-BP1 [XREF_BIBR], another ubiquitin ligase for p53, thus indirectly destabilizing p53 and inhibiting its function.
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USP4 also interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels.
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Recently, ARF-BP1 was reported to specifically target HDAC2 for ubiquitination and degradation and USP4 deubiquitinates and stabilizes ARF-BP1.
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USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels.
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For example, USP4 interacts directly with and deubiquitinates ARF binding protein 1 (ARF-BP1), leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels.
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USP4 has been recently described as a key regulator of p53 stability: USP4 interacts directly and deubiquitylates the E3 HUWE1 (ARF-BP1; MULE), resulting in reduced p53 levels [86].
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USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1.
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Furthermore, USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels [XREF_BIBR].
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Nonetheless, USP4 might deubiquitinate and stabilize both ARF-BP1 and its substrate HDAC2.
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USP4 interacts directly with and deubiquitinates ADP-ribosylatibon factor binding protein 1 (ARFBP1), which results in the stabilization of ARF-BP1 and the subsequent reduction of p53 levels.
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USP4 deubiquitinates TRAF6. 8 / 8
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USP4 interacts with and deubiquitinates TRAF6, thereby preventing the activation of NF-kappaB and AP-1 transcription factors and subsequent immune responses.
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Interestingly, USP4 deubiquitinates not only TRAF2 but also TRAF6 and leads to the regulation of cell migration [12].
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USP4 deubiquitinates TRAF2 and TRAF6, but not TRAF3, and it also rescues IkappaBalpha from degradation in TNFalpha induced HEK cells [XREF_BIBR].
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USP4 deubiquitinates TRAF6 and thereby prevents the activation of NF-kappaB and AP-1 transcription factors and subsequent proinflammatory responses.
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The downregulation of USP4 expression may promote microglial activation and subsequent neuronal inflammation through NF-κB by attenuating the deubiquitination of TRAF6.
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Taken together, these findings suggest that USP4 decreases the polyubiquitination of TRAF6 in a ubiquitin specific domain dependent manner.
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These findings suggest that USP4 deubiquitinates TRAF6 largely in a noncatalytic manner.
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However, there is no evidence of how USP4 deubiquitinates TRAF6 and TRAF2 proteins; our results prove that USP4 targets TRAF6 for K48 linked deubiquitination.
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USP4 deubiquitinates HDAC2. 8 / 8
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Nonetheless, USP4 might deubiquitinate and stabilize both ARF-BP1 and its substrate HDAC2.
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USP4 inhibits p53 and NF-kappaB through deubiquitinating and stabilizing HDAC2.
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Collectively, our data indicate that USP4 deubiquitinates and stabilizes HDAC2 protein.
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Another DUB, USP4 deubiquitinates HDAC2 (Histone deacetylases 2) that was shown to interact with p53 thereby inhibiting the level of acetylated p53.
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Significantly, our results revealed the scaffolding function of TPRS1 in USP4 directed HDAC2 de-ubiquitination and provided new mechanistic insights into the crosstalk between TRPS1, ubiquitin, and histone modification systems leading to tumor growth.
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USP4 suppresses HDAC2 ubiquitination.
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XREF_BIBR, XREF_BIBR Of note, our studies show that USP4 deubiquitinates and stabilizes HDAC2 and the expression of USP4 correlates with that of HDAC2 in cancer tissues (XREF_FIG).
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As we demonstrated that USP4 deubiquitinates HDAC2, it is possible that USP4 can stabilize HDAC2.
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USP4 deubiquitinates IRF4. 5 / 5
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On the whole, our data indicate that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be related to the pathological process of RHD.
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USP4 deubiquitinates IRF4.
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Here, we speculated that USP4 may deubiquitinate IRF4, and affect Th2 cell function and may be associated with the pathogenesis of RHD.
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To conclude, this study indicated that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be associated with the pathological process of RHD.
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USP4 deubiquitinates PRPF31. 5 / 5
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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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Moreover, we found that USP15 and USP4 deubiquitinated substrates PRP31 and PRP3 simultaneously.
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USP15SART3 makes a complex with USP4 and this ternary complex serves as a platform to deubiquitinate PRP31 and PRP3
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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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When PRP31 was ubiquitinated by PRP19, PRP31 was deubiquitinated by USP4.
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USP4 deubiquitinates PTP4A3. 4 / 4
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Specifically, up-regulated USP4 potentiated the growth and invasion of colorectal cancer though deubiquitination and stabilization of PRL-3.19 In addition, USP4 transduced Akt activation to TGF-beta signalling by deubiquitinating and stabilizing TGF-beta type I receptor, thus augmented breast cancer cell invasion and migration.33 These studies demonstrate USP4 as a powerful tumour promoter and an important determinant for canonical oncogenic signalling.
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Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination.
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Deubiquitinating PRL-3 by USP4 leads to AKT activation and E-cadherin reduction in colorectal cancer, where an elevated level of USP4 is associated with tumor size, differentiation, distant metastasis, and poor survival.
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USP4 deubiquitinates CTNNB1. 4 / 4
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In a colon cancer cell line, USP4 deubiquitinates beta-catenin and mediates its nuclear transportation, thus promoting Wnt and beta-catenin signaling and cancer cells growth, migration, and invasion.
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We showed that USP4 deubiquitinates beta-catenin.
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Deubiquitination of beta-catenin by USP4 reverses the ubiquitination mediated degradation of beta-catenin, upregulating Wnt signalling.
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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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USP4 deubiquitinates TRAF2. 4 / 4
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Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFα-induced cancer cell migration
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However, there is no evidence of how USP4 deubiquitinates TRAF6 and TRAF2 proteins; our results prove that USP4 targets TRAF6 for K48 linked deubiquitination.
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USP4 deubiquitinates TRAF2 and TRAF6, but not TRAF3, and it also rescues IkappaBalpha from degradation in TNFalpha induced HEK cells [XREF_BIBR].
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Interestingly, USP4 deubiquitinates not only TRAF2 but also TRAF6 and leads to the regulation of cell migration [12].
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USP4 deubiquitinates DDX58. 4 / 4
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Furthermore, USP4 was found to interact with RIG-I and remove K48-linked polyubiquitination chains from RIG-I.
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USP4 deubiquitinates and stabilizes RIG-I to promote type I IFN induction after viral infection [83].
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Conversely, USP15 and USP4 deubiquitinate TRIM25 and RIG-I, respectively, to stabilize the proteins.
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RIG-I can be ubiquitinated and degraded by RNF125 (Ring Finger Protein 125) and deubiquitinated and stabilized by USP4.
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USP4 deubiquitinates PDPK1. 3 / 3
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In addition, the closely related USP15, which shares 61% amino acid sequence identity with USP4 XREF_BIBR, had no effect on Ub-PDK1 levels, further suggesting that the ability of USP4 to deubiquitinate PDK1 is specific.
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By screening a library of ubiquitin proteases, we further identify the Ubiquitin-Specific Protease 4 (USP4) as an enzyme that removes ubiquitin from PDK1 in vivo and in vitro and co-localizes with PDK1 at the plasma membrane when the two proteins are overexpressed, indicating direct deubiquitination.
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USP4 deubiquitinates PDK1 and co-localizes at the plasma membrane.
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USP4 deubiquitinates TCF4. 3 / 3
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For example, USP4 interacts with and deubiquitinates TCF4, which inhibits beta-catenin-dependent transcription [XREF_BIBR].
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DUBs regulate canonical Wnt signaling, by modulating?β-catenin activity. USP4 deubiquitinases TCF4, to suppress?β-catenin dependent transcription
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USP4 deubiquitinated a subpopulation of TCF4.
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USP4 deubiquitinates HAS2. 3 / 3
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For example, USP4 targets and deubiquitinates hyaluronan synthase 2 (HAS2), but USP4 does not maintain the stability of HAS, and, rather, loss of USP4 increases hyaluronan synthesis [33].
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The de-ubiquitinase USP17 preferentially deconjugated polyubiquitin chains from HAS2, whereas USP4 significantly reduced the monoubiquitination of HAS2; thus, the two DUBs were found to selectively affect the activity and stability of HAS2.
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USP17 efficiently removed polyubiquitination, whereas USP4 preferentially removed monoubiquitination of 6myc-HAS2.;The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function;USP17 and USP4 differently affect HAS2 ubiquitination, and the stability and function of HAS2
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USP4 deubiquitinates TGFB. 3 / 3
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Mechanistically, hepatocyte USP4 directly bound to and deubiquitinated transforming growth factor-beta activated kinase 1 (TAK1), leading to a suppression of the activation of downstream NF-kappaB and JNK cascades, which in turn reversed the disruption of the IRS-AKT-GSK3beta signaling.
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The authors further go on to show that USP4 was able to deubiquitylate the TGF-beta receptor I (TbetaRI) directly and rescue it from proteasome mediated degradation.
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USP4 has been reported to enhance TGFbeta signalling by directly interacting with and deubiquitylating type I TGFbeta receptor, ALK5 XREF_BIBR.
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USP4 leads to the deubiquitination of SMAD4. 2 / 2
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USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling.
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We demonstrated that ubiquitin-specific protease (USP) 4 strongly induces activin/BMP signaling by removing the inhibitory monoubiquitination from SMAD4.
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USP4 deubiquitinates E3_Ub_ligase. 2 / 2
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In contrast to USP2a, USP4 deubiquitinates and stabilizes a different E3 that ubiquitinates p53 called ARF-BP1, thereby destabilizing p53 [XREF_BIBR].
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USP4 interacts with and deubiquitylates another E3 ubiquitin ligase for p53, ARF-BP1/Mule/HUWE, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels.
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Modified USP4 leads to the deubiquitination of MAP3K7. 2 / 2
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Overexpression of USP4 wild-type, but not deuibiquitinase deficient C311A mutant, inhibits both TNFalpha- and TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-kappaB activation.
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As shown in XREF_FIG, overexpression of USP4 wild-type but not deubiquitinase deficient C311A mutant abrogated TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination.
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USP4 deubiquitinates TRIM21. 2 / 2
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Oncogenic protein UnpEL/Usp4 deubiquitinates Ro52 by its isopeptidase activity
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Oncogenic protein UnpEL and Usp4 deubiquitinates Ro52 by its isopeptidase activity.
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USP4 deubiquitinates adenosine on A2. 2 / 2
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In contrast to these observations, the deubiquitination of the adenosine A 2A receptor (A 2A R) by USP4 is necessary for the cell surface delivery of a functionally active receptor (XREF_FIG, pathway 4) [XREF_BIBR].
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The Adenosine A2 receptor is deubiquitinated by USP4; the ubiquitination status and trafficking of the EGFR growth factor receptor is regulated by the USP8 and STAM complex; the beta2-AR undergoes increased agonist stimulated ubiquitination, lysosomal trafficking, and degradation after knockdown of USPs 20 and 33.
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USP4 deubiquitinates INS. 2 / 2
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USP4 is a deubiquitinating enzyme and may deubiquitinate insulin receptors to inhibit their degradation, which maintains the expression level of insulin receptors on the membrane surface and improves insulin resistance.
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Upregulation of USP4 reduces the ubiquitination and degradation of insulin receptors, upregulates the level of insulin receptors, and ultimately improves insulin resistance.
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USP4 deubiquitinates ADORA2A. 1 / 1
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No evidence text available
USP4 deubiquitinates TRAF6 on lysine. 1 / 1
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No evidence text available
Modified USP4 leads to the deubiquitination of NFkappaB. 1 / 1
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Overexpression of USP4 wild-type, but not deuibiquitinase deficient C311A mutant, inhibits both TNFalpha- and TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-kappaB activation.
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USP4 leads to the deubiquitination of DVL. 1 / 1
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USP4 was initially identified as a repressor of the Wnt and beta-catenin signaling pathway, given that USP4 can mediate deubiquitination and stabilization of Dvl, a key molecule involved in the turnover of cytosolic beta-catenin.
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Modified USP4 leads to the deubiquitination of AQP2. 1 / 1
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Taken together, the data suggest that USP4 is a key regulator of AQP2 deubiquitylation and that loss of USP4 leads to increased AQP2 ubiquitylation, decreased AQP2 levels, and decreased cell surface AQP2 accumulation upon VP treatment.
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USP4 deubiquitinates RB1. 1 / 1
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USP4, reported as an oncogenic protein, is known to interact with the pocket proteins (Rb, p107, and p130) although no deubiquitinating activity has been reported
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USP4 deubiquitinates IRF8. 1 / 1
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In the present study, we demonstrate that ubiquitin-specific protease (USP)4 physically interacted with interferon regulatory factor 8 (IRF8) function via a K48-linked deubiquitinase, which stabilized IRF8 protein levels in Treg cells.
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USP4 deubiquitinates signaling receptor activity on A2. 1 / 1
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USP4 has been shown to deubiquitinate A 2a receptor, a G S -coupled receptor at the cell surface, and deubiquitination of A 2a receptor by USP4 enhanced cell surface expression of the receptor in cult[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP4-C311A leads to the deubiquitination of JNK. 1 / 1
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USP4 (C311A) mutation did not inhibit the TAK1 polyubiquitination, and phosphorylation of TAK1, = JNK1/2, and p38 in angiotensin treated myocytes.
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USP4 deubiquitinates RNPS1. 1 / 1
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Although RNPS1 is polyubiquitinated by both K48- and K63-linkages, USP4 exclusively deubiquitinates K63-linked polyubiquitin chains of RNPS1.
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USP4 deubiquitinates NR2C2. 1 / 1
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Mechanistically, hepatocyte USP4 directly bound to and deubiquitinated transforming growth factor-β activated kinase 1 (TAK1)
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USP4 leads to the deubiquitination of NFKBIA. 1 / 1
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Therefore, we further analyzed the effect of USP4 knockdown on the TNFalpha induced IKK phosphorylation, IkappaBalpha phosphorylation, ubiquitination and degradation.
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USP4 deubiquitinates RBBP8. 1 / 1
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Although USP4 does not directly deubiquitinate CtIP, its interaction with CtIP is essential for HR as blocking their binding reduces HR efficiency.
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USP4 deubiquitinates RBL1. 1 / 1
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USP4, reported as an oncogenic protein, is known to interact with the pocket proteins (Rb, p107, and p130) although no deubiquitinating activity has been reported
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USP4 deubiquitinates TRAF3. 1 / 1
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USP4 deubiquitinates TRAF2 and TRAF6, but not TRAF3, and it also rescues IkappaBalpha from degradation in TNFalpha induced HEK cells [XREF_BIBR].
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USP4 deubiquitinates USP4. 1 / 1
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UnpEL/Usp4 is ubiquitinated by Ro52 and deubiquitinated by itself
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USP4 deubiquitinates AQP2. 1 / 1
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AQP2 and USP4 co-immunoprecipitated from mpkCCD14 cells and mouse kidney, and in vitro, USP4 can deubiquitylate AQP2.
30901874
USP4 deubiquitinates TRAF2 on lysine. 1 / 1
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biopax:reactome
No evidence text available
USP4 deubiquitinates BIRC2. 1 / 1
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In contrast, USP4 wild-type failed to deubiquitinate cIAP1 (XREF_SUPPLEMENTARY).
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USP4 deubiquitinates TGFBR. 1 / 1
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The authors further go on to show that USP4 was able to deubiquitylate the TGF-beta receptor I (TbetaRI) directly and rescue it from proteasome mediated degradation.
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USP4 deubiquitinates RIPK1. 1 / 1
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USP4 directly interacts with receptor-interacting protein 1 (RIP1) and deubiquitinates K63-linked ubiquitination from RIP1.
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USP4 deubiquitinates PPIA. 1 / 1
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Mechanistically, cyclophilin A (CypA) was identified as an important molecule for USP4-mediated oncogenic activity in HCC.
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USP4 deubiquitinates TP53. 1 / 1
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Regulation of p53 is also subject to other DUBs, such as USP4, USP10, USP29, and USP42 [171].
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USP4 deubiquitinates DDX58 on K48. 1 / 1
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USP4, it positively regulates the RIG-I-mediated antiviral response by deubiquitinating K48-linked ubiquitin chains and stabilizing RIG-I (77).
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USP4 deubiquitinates RIPK1 on K377. 1 / 1
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USP4 deubiquitinates RBL2. 1 / 1
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USP4, reported as an oncogenic protein, is known to interact with the pocket proteins (Rb, p107, and p130) although no deubiquitinating activity has been reported
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Modified USP4 leads to the deubiquitination of HDAC2. 1 / 1
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As shown in XREF_FIG, overexpression of USP4-WT but not C311A mutant abrogated HDAC2 polyubiquitination.
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USP4 deubiquitinates Histone. 1 / 1
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Another DUB, USP4 deubiquitinates HDAC2 (Histone deacetylases 2) that was shown to interact with p53 thereby inhibiting the level of acetylated p53.
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USP4 deubiquitinates RORC. 1 / 1
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Ubiquitin-specific protease 4 promotes Th17 cell function under inflammation by deubiquitinating and stabilizing RORγt
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USP4 leads to the deubiquitination of IKK_complex. 1 / 1
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Therefore, we further analyzed the effect of USP4 knockdown on the TNFalpha induced IKK phosphorylation, IkappaBalpha phosphorylation, ubiquitination and degradation.
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USP4-C311A leads to the deubiquitination of p38. 1 / 1
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USP4 (C311A) mutation did not inhibit the TAK1 polyubiquitination, and phosphorylation of TAK1, = JNK1/2, and p38 in angiotensin treated myocytes.
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USP4 leads to the deubiquitination of RHEB. 1 / 1
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Thus, we propose a mechanistic model whereby Rheb mediated mTORC1 activation is dictated by a dynamic opposing act between Rheb ubiquitination and deubiquitination that are catalyzed by RNF152 and USP4 respectively.
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USP4 deubiquitinates MAP3K7 on K63. 1 / 1
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USP4 deubiquitinates TAK1 with Lys63 linked polyubiquitination and inhibits Dox induced NF-kappaB activation.
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USP4-C311A leads to the deubiquitination of MAP3K7. 1 / 1
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USP4 (C311A) mutation did not inhibit the TAK1 polyubiquitination, and phosphorylation of TAK1, = JNK1/2, and p38 in angiotensin treated myocytes.
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USP4 deubiquitinates Interferon. 1 / 1
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We speculated that ubiquitin specific peptidase4 (USP4) may deubiquitinate interferon regulatory factor4 (IRF4) and affect Thelper type2 (Th2) cell function.
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USP4 deubiquitinates TRIM25. 1 / 1
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Conversely, USP15 and USP4 deubiquitinate TRIM25 and RIG-I, respectively, to stabilize the proteins.
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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
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In addition, by inducing USP4 overexpression (using a USP4 overexpression plasmid) or the knockdown of USP4 (by transfection with a USP4 shRNA plasmid), we found that USP4 inhibited cell proliferation in vitro.
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These data demonstrate that USP4 suppresses the proliferation of breast cancer cells through the upregulation of PDCD4.
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The findings showed that the expression of TGF-betaR1 and USP4 were increased in hypertrophic scar tissues and fibroblasts, and that down-regulating USP4 inhibited hypertrophic scar fibroblast proliferation and migration and induced cell apoptosis in vitro.
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To determine whether PDCD4 is involved in the anti-proliferative function of USP4, we further examined the role of PDCD4 in the USP4 induced inhibition of proliferation by knocking down PDCD4 using siRNA.
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The Cell Counting Kit-8 (CCK-8) assay results showed that the proliferation of hypertrophic scar fibroblasts transfected with siUSP4 was significantly inhibited on the fifth and seventh day, indicating that down-regulation of USP4 could suppress the proliferation of hypertrophic scar fibroblasts.
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These results indicated that USP4 markedly inhibited breast cancer cell proliferation and colony forming ability.
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We also demonstrate that USP4 inhibits breast cancer cell proliferation.
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Thus, in this study, we wished to determine whether PDCD4 is involved in the USP4 mediated inhibition of breast cancer cell proliferation.
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USP4 inhibits breast cancer cell proliferation through the upregulation of PDCD4.
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These results indicated that USP4 markedly inhibited breast cancer cell proliferation and colony-forming ability.
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In vitro study showed that knockdown of USP4 inhibited PC cells proliferation, migration and invasion.
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USP4 and S1P1 were up-regulated in mesenchymal-type liver-tumor cells with miR-148a dysregulation, facilitating migration and proliferation of tumor cells.
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Taken together, CypA is indispensable for USP4 mediated cell proliferation in HCC.
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XREF_BIBR also demonstrated that inhibiting USP4 expression in GBM cells both inhibited their proliferation and induced apoptosis via antagonizing USP4 mediated stimulation of the ERK signaling pathway.
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By promoting activation of the relaxin and TGF-beta 1/Smad2/matrix metalloproteinase 9 axis and transcriptional repression activity of HDAC2, USP4 induces breast cell invasion, migration, and proliferation both in vitro and in vivo.
33681193
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Moreover, knockdown of USP4 could significantly inhibit cell proliferation and increase cell apoptosis in U87 and T98G cells.
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As shown in XREF_FIG, the inhibition of cell proliferation that was induced by USP4 overexpression was markedly reversed following PDCD4 knockdown using siRNA.
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In summary, these data indicate that USP4 enhances HCC cell proliferation, migration, and invasion and suppresses HCC cell apoptosis in vitro.
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USP4 accelerates HCC cell proliferation, migration, and invasion in vitro.
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To test this hypothesis, CCK-8 assays were used to investigate the effects of CypA on USP4 induced proliferation of HCC cell lines.
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USP4 affects NFkappaB
| 1 3 28
USP4 inhibits NFkappaB.
| 1 20
USP4 inhibits NFkappaB. 10 / 23
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238 Recently, USP4 has been identified as a new DUB of TRAF6 and can negatively regulate the NF-kappaB signaling pathway.
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USP4 inhibits NF-kappaB transcriptional activity through HDAC2.
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To further explore the role of USP4 on NF-kappaB target gene expression, we examined the effect of USP4 knockdown on the expression of other TNFalpha induced NF-kappaB target genes.
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USP4 inhibits p53 and NF-kappaB through deubiquitinating and stabilizing HDAC2.
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In addition, USP4 inhibits TNF-alpha-induced activation of NF-kappaB through USP4 deubiquitination of TAK1 XREF_BIBR.
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XREF_BIBR showed that USP4 could block Dox induced activation of NF-kappaB at the early stage of the treatment by preventing TAK1 from conjugating K63 linked polyubiquitin chains.
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Also, USP4 de-ubiquitinated and then inhibited the activation of p53 and NF-kappaB [XREF_BIBR].
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It was also found that USP4 inhibited NF-kappaB activation, but in this study we confirmed that USP4 positively regulates the NF-kappaB signalling pathway during EV71 infection.
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Consistent with this, the results of Hou et al. 28 showed that USP4 promotes apoptosis and inhibits NF-kappaB activation in head and neck squamous cell carcinoma.
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USP4 acts as a TAK1 Lys63 specific deubiquitinase to deubiquitinate TAK1 and inhibit Dox induced NF-kappaB activation.
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Modified USP4 inhibits NFkappaB. 1 / 1
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Ectopic expression of USP4 inhibits the TRAF2- and TRAF6 stimulated NF-kappaB reporter gene and negatively regulates the TNFalpha induced IkappaBalpha (inhibitor of NF-kappaBalpha) degradation and NF-kappaB activation.
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USP4 bound to RIPK1 inhibits NFkappaB. 1 / 1
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An association between USP4 and RIP1 was reported to impair NF-kappaB activation and exacerbate TNF-alpha-induced apoptosis in head and neck squamous cell carcinoma (HNSCC).
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USP4 activates NFkappaB.
| 1 2 8
USP4 activates NFkappaB. 10 / 11
| 1 2 8
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Therefore, to further confirm USP4-induced NF-κB activation, we designed and synthesized two siRNAs to knock down the intrinsic expression of USP4.
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These results suggest that deubiquitinating enzyme activity is responsible for the suppression of TNFα-mediated NF-κB activation by USP4.
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Hence, USP4 positively regulates NF-kappaB signaling by deubiquitinating K48-ubiquitin chains of TRAF6 in EV71 infection [XREF_BIBR].
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Our findings provide novel insights into the molecular mechanisms by which USP4 positively regulates NF-kappaB signalling and thus plays a critical role in maintaining the balance between innate immune responses and immune tolerance.
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Although USP4 / UNP is associated with the TNF response and activates NF-kappaB as shown with USP2a , it has a different role , wherein USP4 regulates TAK-1 stability upon TNF response .
| PMC
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Knockdown of USP4 promoted IL-1beta, LPS, and TGF-beta-induced NF-kappaB activation (Fan et al., 2011).
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USP4 positively regulates the antiviral NF-kappaB pathway.
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In addition to these newly identified nuclear functions, both USP4 and USP15 are well known to function in the cytosol, i.e. USP4 modulates the Wnt and beta-catenin, NF-kappaB, p53 and TGF-beta signaling pathways while USP15 performs functions in the TGF-beta receptor and NF-kappaB signaling pathways.
27060135
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It was also found that USP4 inhibited NF-kappaB activation, but in this study we confirmed that USP4 positively regulates the NF-kappaB signalling pathway during EV71 infection.
30194441
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Therefore, to further confirm USP4 induced NF-kappaB activation, we designed and synthesized two siRNAs to knock down the intrinsic expression of USP4.
30194441
USP4 affects TP53
| 1 3 19
USP4 inhibits TP53.
| 1 3 10
USP4 inhibits TP53. 10 / 19
| 1 3 10
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Furthermore, we demonstrated that USP4 inhibited p53 mediated transcriptional activity in wild-type but not HDAC2 knockdown U2OS cells in response to DNA damage or not (XREF_FIG).
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Increased ARF-BP1 and Mule degradation causes p53 stabilization, which is antagonized by the DUBs USP7 and USP4.
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USP4 could inhibit p53 through deubiquitinating and stabilizing ARF-BP1 xref or HDAC2 xref and was upregulated in several cancer tissues.
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USP4 inhibits p53- and p53-mediated apoptosis, regulates NF-κB signaling pathway and modulates TGFβ signaling, xref , xref , xref , xref promoting breast cancer xref and lung adenocarcinoma invasiveness. xref We demonstrate here that both USP17 and USP4 are expressed at higher levels in breast and lung cancer cell lines compared to normal cells.
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Previous study has also demonstrated that USP4 inhibits p53 functions by deubiquitinating HDAC [80].
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Also, USP4 de-ubiquitinated and then inhibited the activation of p53 and NF-kappaB [XREF_BIBR].
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Recently, it has been reported that USP4 could antagonize p53 signalling through its deubiquitinating activity.15, 18 Given that Bax and Bcl2 are 2 canonical downstream regulators of p53 in mediating cell apoptosis and were regulated by USP4 in response to cisplatin treatment, we speculated that pro survival effect of USP4 in response to cisplatin treatment may be associated with p53 signalling pathway.
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Because USP4 inhibits ubiquitination-mediated HDAC2 degradation, we hypothesized that USP4 inhibits p53 functions through HDAC2.
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USP4 inhibits p53 transcriptional activation via stabilizing HDAC2 and ARF-BP1, which acts as a deacetylase and E3 ubiquitin ligase of p53, respectively.
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USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1.
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USP4 activates TP53.
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USP4 activates TP53. 6 / 6
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However, in response to cisplatin treatment, USP4 deficiency significantly augmented melanoma cells apoptosis by activating p53 signalling.
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However, in response to cisplatin induced stress, the knockdown of USP4 could markedly increase the apoptotic rate of melanoma cells, and USP4 deficiency sensitized melanoma cell to cisplatin induced apoptosis by activating p53 pathway.
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In contrast, silencing USP4 by shRNA remarkably increased the p53 activity in response to DNA damage or not (XREF_FIG).
26411366
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In addition to these newly identified nuclear functions, both USP4 and USP15 are well known to function in the cytosol, i.e. USP4 modulates the Wnt and beta-catenin, NF-kappaB, p53 and TGF-beta signaling pathways while USP15 performs functions in the TGF-beta receptor and NF-kappaB signaling pathways.
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Notably, studies have also indicated functions for USP4 in regulating growth factor signalling by the Toll-like receptor/IL1 pathway [88] , TGFb receptor type I [89, 90] , TNFa receptor [91] , growth factoractivated kinase regulation [92] and Wnt signalling [93] , making USP4 a prime target for further evaluation as an oncology drug target with strong potential in DDR contexts.Depletion of USP5 has been reported to cause accumulation of nuclear p53 and increase p53 transcriptional activity.
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Similarly, knockdown of USP4 significantly decreases cell viability in a p53 dependent manner after treating GMB cells with temozolomide.
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USP4 decreases the amount of TP53.
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USP4 decreases the amount of TP53. 2 / 3
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In fact, our data show that USP4 inhibited the levels of acetylation but not protein expression of p53 (XREF_FIG).
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For instance, USP4 was shown to reduce p53 levels via deubiquitination of ARF-BP1 XREF_BIBR.
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USP4 increases the amount of TP53.
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USP4 increases the amount of TP53. 1 / 1
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More importantly, in response to cisplatin treatment, USP4 deficiency resulted in up-regulation of p53 expression both at transcriptional level and translational level.
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USP4 affects CTNNB1
| 2 17
USP4 activates CTNNB1.
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USP4 activates CTNNB1. 10 / 14
| 2 8
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In addition to these newly identified nuclear functions, both USP4 and USP15 are well known to function in the cytosol, i.e. USP4 modulates the Wnt and beta-catenin, NF-kappaB, p53 and TGF-beta signaling pathways while USP15 performs functions in the TGF-beta receptor and NF-kappaB signaling pathways.
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For instance, USP4 promote tumor progression by regulating beta-Catenin Signaling XREF_BIBR.
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The assay results revealed that transcriptional activity increases in proportion to the amount of USP4 in the nucleus, which suggests that USP4 enhances beta-catenin activity by facilitating its trans[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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This observation raised the possibility that USP4 dependent activation of beta-catenin is not only caused by the catalytic activity of USP4 but also mediated by another mechanism such as a nuclear tra[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Interestingly, it was also found that knockdown of USP4 decreased the level of beta-catenin protein without changes in its mRNA level (XREF_FIG).
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In the present study, we found that the USP4 and beta-catenin axis was involved in metastatic potential through USP4 mediated stabilization of beta-catenin and that knockdown of USP4 and beta-catenin suppressed the metastatic potential including clonogenicity, migration, and invasion, and induced MET by downregulating ZEB1 expression.
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However, stabilized β-catenin was partially affected by the USP4 expression level ( Figure 2 F), and the catalytically defective C311A USP4 was able to activate β-catenin to some extent ( Figure 2 A).
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This observation raised the possibility that USP4-dependent activation of β-catenin is not only caused by the catalytic activity of USP4 but also mediated by another mechanism such as a nuclear transp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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These results confirm that USP4 knockdown suppresses the transcriptional activity of beta-catenin, thereby supporting the suggestion that USP4 functions as a positive regulator of the WNT and beta-cat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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However, USP4 had no effect on the stability of GSK3beta, a negative regulator of beta-catenin, suggesting that USP4 enhances the stability and activity of beta-catenin not by affecting beta-catenin r[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP4-C311A activates CTNNB1. 1 / 1
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However, stabilized beta-catenin was partially affected by the USP4 expression level, and the catalytically defective C311A USP4 was able to activate beta-catenin to some extent.
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USP4 increases the amount of CTNNB1.
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USP4 increases the amount of CTNNB1. 5 / 5
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USP4 increased the level of beta-catenin by inducing its deubiquitinylation.
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To verify that USP4 induces EMT process by upregulating beta-catenin expression, we checked the expression level of ZEB1 and E-cadherin in USP4 overexpressing PC14PE6 cells (XREF_FIG).
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Based on the above results, we found that beta-catenin was involved in the metastatic potential of PC14PE6 and LvBr4 cells and that USP4 upregulated the expression of beta-catenin by deubiquitinylating beta-catenin.
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As expected, knockdown of USP4 significantly downregulated the expression of beta-catenin (XREF_FIG) and suppressed the invasiveness of PC14PE6 and LvBr5-Luc cells (XREF_FIG).
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beta-Catenin protein stability was significantly lower in USP4 silenced PC14PE6 and LvBr4 cells than in PC14PE6 cells (XREF_FIG), demonstrating that USP4 positively regulated beta-catenin expression in metastatic lung cancer cells.
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Modified USP4 increases the amount of CTNNB1. 1 / 1
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To examine whether USP4 overexpression increases beta-catenin expression and invasiveness, PC14PE6 cells were transfected with blank (FLAG) and USP4-overexpression vector (FLAG-USP4).
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USP4 inhibits CTNNB1.
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USP4 inhibits CTNNB1. 1 / 1
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In this study, we found ubiquitin specific peptidase 4 (USP4) to strongly inhibit the Wnt and beta-catenin signaling by removing Lysine 63 linked poly-ubiquitin chain from Dishevelled (Dvl).
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Modified USP4 inhibits CTNNB1. 1 / 1
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Ectopic expression of USP4 promoted beta-catenin poly-ubiquitination and thus inhibited Wnt induced accumulation of cytosolic beta-catenin and counteracted Wnt induced transcriptional activity.
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USP4 affects Neoplasm Invasiveness
| 1 21
USP4 activates Neoplasm Invasiveness.
| 1 20
USP4 activates Neoplasm Invasiveness. 10 / 20
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USP4 accelerates the growth, invasion, and metastasis of colorectal cancer [XREF_BIBR, XREF_BIBR].
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In summary, these data indicate that USP4 enhances HCC cell proliferation, migration, and invasion and suppresses HCC cell apoptosis in vitro.
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As we have discussed above, USP4 can target the TGF-beta type I receptor and promote invasion and metastasis of breast cancer and high USP15 expression correlated with enhanced pSmad2 expression in ti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
27155333
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Subsequently , Cao et al. further confirmed that USP4 can promote cell migration and invasion through relaxin / TGF-beta1 / smad2 / matrix metalloprotein-9 signaling pathway [ 92 ] .
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Moreover, USP4 upregulation promoted Huh7 and PLC/PRF/5 cell migration and invasion ability (P < 0.01 for all).
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Using gene interference, we demonstrated that USP4 knockdown significantly inhibited HCC cell migration and invasion in vitro, and USP4 overexpression had the opposite results.
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Using in vitro and in vivo assays, we demonstrated that USP4 overexpression enhanced HCC cell growth, migration, and invasion.
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By promoting activation of the relaxin and TGF-beta 1/Smad2/matrix metalloproteinase 9 axis and transcriptional repression activity of HDAC2, USP4 induces breast cell invasion, migration, and proliferation both in vitro and in vivo.
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Consistent with this correlation, USP4 knockdown in HCT116, a colon cancer cell line, reduced invasion and migration activity.
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USP4 accelerates HCC cell proliferation, migration, and invasion in vitro.
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Modified USP4 activates Neoplasm Invasiveness. 1 / 1
| 1
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To examine whether USP4 overexpression increases beta-catenin expression and invasiveness, PC14PE6 cells were transfected with blank (FLAG) and USP4-overexpression vector (FLAG-USP4).
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USP4 inhibits Neoplasm Invasiveness.
| 1
USP4 inhibits Neoplasm Invasiveness. 1 / 1
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Interestingly, we were also able to observe that USP4 knockdown in SW480 cells increased invasion activity under the same experimental conditions as used in HCT116 cells, suggesting that the role of U[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP4 affects HDAC2
| 4
USP4 activates HDAC2.
| 3
USP4 activates HDAC2. 3 / 8
| 3
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In fact, expression of USP4 significantly prolonged the half-life of HDAC2 (XREF_FIG).
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Moreover, we found that USP4 targets HDAC2 to downregulate tumor necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation.
26411366
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By promoting activation of the relaxin and TGF-beta 1/Smad2/matrix metalloproteinase 9 axis and transcriptional repression activity of HDAC2, USP4 induces breast cell invasion, migration, and proliferation both in vitro and in vivo.
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USP4 inhibits HDAC2.
| 1
USP4 inhibits HDAC2. 1 / 7
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Therefore, our studies reveal USP4 suppresses p53 and NF-kappaB activation by stabilizing HDAC2.
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USP4 affects TGFB
| 15
USP4 activates TGFB.
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USP4 activates TGFB. 10 / 11
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By promoting activation of the relaxin and TGF-beta 1/Smad2/matrix metalloproteinase 9 axis and transcriptional repression activity of HDAC2, USP4 induces breast cell invasion, migration, and proliferation both in vitro and in vivo.
33681193
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Of the newly identified two targets of miR-148a (i.e., USP4 and S1P1), USP4 overexpression contributed to HCC progression toward more aggressive feature by facilitating TGF-beta signaling pathways, growth advantage and migrating capability.
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The hypothesis that drove this study was that USP4 might also mediate the TGF-beta signal transduction pathway in hypertrophic scar fibroblasts.
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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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USP4 promotes TGF-beta signals by stabilizing TGF-betatype I rceptor (TbetaRIota) [XREF_BIBR].
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Collectively, our results support the concept that dysregulation of miR-148a is associated with the poor prognosis of HCC and may account for the tumor progression to advanced stages, and that, of the newly identified targets, USP4 overexpression may contribute to HCC progression towards more aggressive feature presumably by facilitating TGF-beta signaling pathways, growth advantage and migrating capability.
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USP4 promotes invasion of breast cancer cells via Relaxin and TGF-beta 1/Smad2/MMP -9 signal.
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Ubiquitin specific protease 4 (USP4) augments TGF-beta signaling through the prevention of TGF-beta RI degradation.
26583078
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In addition to these newly identified nuclear functions, both USP4 and USP15 are well known to function in the cytosol, i.e. USP4 modulates the Wnt and beta-catenin, NF-kappaB, p53 and TGF-beta signaling pathways while USP15 performs functions in the TGF-beta receptor and NF-kappaB signaling pathways.
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USP4, when overexpressed, potently enhanced TGF-beta signaling.
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USP4 bound to TGFBR1 activates TGFB. 2 / 2
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Mechanistically, we revealed that USP4 interacted directly with and deubiquitinated TGF-beta receptor type I (TGFR-1) to activate the TGF-beta signaling pathway, and subsequently induced the Epithelial-Mesenchymal Transition (EMT) in HCC cells.
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Taken together, our results elucidate that USP4 is highly expressed in HCC and promotes the tumor invasion and metastasis, the underlying mechanism is that USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-beta signaling Induced EMT.
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USP4 inhibits TGFB.
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USP4 inhibits TGFB. 2 / 2
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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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H19 functions as a competing endogenous RNA (ceRNA) by sponging miR-148a and maintaining the expression levels of ubiquitin specific protease 4 (USP4), a key miR-148a target that stabilizes TGFbetaRI and promotes TGF-beta signalling.
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USP4 affects cell migration
| 1 12
USP4 activates cell migration.
| 1 7
USP4 activates cell migration. 8 / 8
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USP4 has also been shown to target TRAF2 and TRAF6 inhibiting nuclear factor-kappaB (NF-kB) signalling and antagonizing lung cancer cell migration XREF_BIBR XREF_BIBR XREF_BIBR, suggesting a context dependent role in cancer.
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Collectively, these data demonstrated that USP4 promotes melanoma cell migration and invasion by promoting EMT.
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The migration and invasion assays showed that USP4 promotes human breast cancer cell migration and invasion by USP4 overexpression, and knockdown of USP4 by siRNA inhibits human breast cancer cell migration and invasion.
27049265
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Using gene interference, we demonstrated that USP4 knockdown significantly inhibited HCC cell migration and invasion in vitro, and USP4 overexpression had the opposite results.
30335615
eidos
Subsequently , Cao et al. further confirmed that USP4 can promote cell migration and invasion through relaxin / TGF-beta1 / smad2 / matrix metalloprotein-9 signaling pathway [ 92 ] .
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Transwell assays showed that USP4 knockdown inhibited cell migration and invasion in MHCC97H and LM3 cells.
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In addition, USP4 depletion inhibits breast cancer cell migration, which is induced by AKT [13].
| PMC
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Moreover, USP4 upregulation promoted Huh7 and PLC/PRF/5 cell migration and invasion ability (P < 0.01 for all).
29396555
USP4 inhibits cell migration.
| 5
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Moreover, AKT induced breast cancer cell migration was inhibited by USP4 depletion and TbetaRI kinase inhibition.
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USP4 has previously been confirmed to target TRAF2 and TRAF6 for deubiquitination and it has been established that USP4 inhibits TNFalpha induced cancer cell migration 35.
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Also, the in vitro wound healing assay for cell migration showed that low expression of USP4 reduced cell migration.
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AKT induced breast cancer cell migration could be inhibited by depletion of USP4 (Zhang et al., 2012).
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However, in breast cancer, USP4 was also recognized as a tumour suppressor for its up-regulatory effect on programmed cell death 4 (PDCD4) to restrain tumour growth.20 Moreover, USP4 was able to target TRAF2 and TRAF6 for deubiquitination and thereafter inhibited TNFalpha induced cancer cell migration.34 In the present study, we proved that USP4 expression was drastically increased in melanoma.
29542252
USP4 affects apoptotic process
| 12
USP4 activates apoptotic process.
| 7
USP4 activates apoptotic process. 7 / 8
| 7
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Consistent with this, the results of Hou et al. 28 showed that USP4 promotes apoptosis and inhibits NF-kappaB activation in head and neck squamous cell carcinoma.
29396555
reach
Moreover, knockdown of USP4 could significantly inhibit cell proliferation and increase cell apoptosis in U87 and T98G cells.
30881035
reach
However, in response to cisplatin induced stress, the knockdown of USP4 could markedly increase the apoptotic rate of melanoma cells, and USP4 deficiency sensitized melanoma cell to cisplatin induced apoptosis by activating p53 pathway.
29542252
reach
The findings showed that the expression of TGF-betaR1 and USP4 were increased in hypertrophic scar tissues and fibroblasts, and that down-regulating USP4 inhibited hypertrophic scar fibroblast proliferation and migration and induced cell apoptosis in vitro.
32308208
reach
However, in response to cisplatin treatment, USP4 deficiency significantly augmented melanoma cells apoptosis by activating p53 signalling.
29542252
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We subsequently showed that USP4 regulated cisplatin induced cell apoptosis via p53 signalling.
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USP4 knockout mice exhibited exacerbated hepatic I/R injury, as evidenced by enhanced liver inflammation via the NF-kappaB signalling pathway and increased hepatocyte apoptosis.
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USP4 inhibits apoptotic process.
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Additionally, USP4 overexpression inhibited hepatocyte inflammation and apoptosis on hepatic I/R stimulation.
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In summary, these data indicate that USP4 enhances HCC cell proliferation, migration, and invasion and suppresses HCC cell apoptosis in vitro.
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We then tested whether USP4 expression inhibits cell apoptosis upon DNA damage.
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XREF_BIBR also demonstrated that inhibiting USP4 expression in GBM cells both inhibited their proliferation and induced apoptosis via antagonizing USP4 mediated stimulation of the ERK signaling pathway.
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It was found that over-expression of USP4 enhanced the ability of RD cells to fight against invading EV71, and also reduced cell apoptosis.
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USP4 affects Neoplasm Metastasis
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USP4 activates Neoplasm Metastasis.
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Using bioluminescence imaging, we found that knockdown of USP4 suppressed brain metastasis in vivo and significantly increased overall survival and brain metastasis-free survival.
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In addition , USP4 reportedly mediates cell proliferation , survival and metastasis ( 32 , 33 ) .
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As we have discussed above, USP4 can target the TGF-beta type I receptor and promote invasion and metastasis of breast cancer and high USP15 expression correlated with enhanced pSmad2 expression in ti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP4 accelerates the growth, invasion, and metastasis of colorectal cancer [XREF_BIBR, XREF_BIBR].
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Luminescence imaging experiments indicated that knockdown of USP4 suppressed brain metastasis in vivo and promoted the overall survival and brain metastasis-free survival.
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Moreover, USP4 is recently showed to enhance EMT and metastasis by stabilizing TbetaRI [XREF_BIBR].
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In vivo, we also found that USP4 knockdown obviously blocked HCC cell metastasis.
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Inhibition of USP4 would be expected to inhibit the invasion and metastasis of breast cancer and drugs that target USP15 could reduce the oncogenic potential of glioblastomas.
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Further, we investigated the mechanism by which USP4 promotes growth and metastasis in HCC cells.
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USP4 can promote TGF-beta-induced invasion and metastasis of breast cancer cells in a zebrafish xenograft model.
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USP4 inhibits Neoplasm Metastasis.
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USP4 inhibits Neoplasm Metastasis. 2 / 2
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Further, the effect of USP4 on biological function investigated in HCC cell lines showed that USP4 knockdown significantly impaired HCC cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth and intrahepatic metastasis in vivo.
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Knockdown of USP4 dramatically suppressed the metastasis of PC14PE6 and LvBr5-Luc cells to the whole body and brain, as reflected by bioluminescence signals at 19 and 22 days post-injection (XREF_FIG).
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USP4 affects MAP3K7
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USP4 inhibits MAP3K7.
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USP4 inhibits MAP3K7. 4 / 10
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We also found that overexpression of USP4 inhibited TAK1 but not IKKβ-induced NF-κB activation in a reporter assay ( xref ).
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USP4 inhibits TAK1 and TAB1 co-overexpression-mediated NF-kappaB activation.
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We also found that overexpression of USP4 inhibited TAK1 but not IKKβ-induced NF-κB activation in a reporter assay ( xref ).
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XREF_BIBR showed that USP4 could block Dox induced activation of NF-kappaB at the early stage of the treatment by preventing TAK1 from conjugating K63 linked polyubiquitin chains.
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USP4 activates MAP3K7.
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USP4 activates MAP3K7. 2 / 2
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Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor beta activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo.
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Previous study also showed that USP4 targets TAK1 by removing K63 linked polyubiquitination and then recruit IkappaB kinase (IKK) complex to simulate TNF-alpha -induced NF-kappaB activation 49.
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USP4 affects TRAF6
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USP4 activates TRAF6.
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USP4 activates TRAF6. 7 / 7
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USP4 has also been shown to target TRAF2 and TRAF6 inhibiting nuclear factor-kappaB (NF-kB) signalling and antagonizing lung cancer cell migration XREF_BIBR XREF_BIBR XREF_BIBR, suggesting a context dependent role in cancer.
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USP4 has previously been confirmed to target TRAF2 and TRAF6 for deubiquitination and it has been established that USP4 inhibits TNFalpha induced cancer cell migration 35.
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However, when the RD cells were transfected with a plasmid bearing USP4, the results show that USP4 could decrease the degradation of TRAF6 and also inhibit the replication of EV71.
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However, there is no evidence of how USP4 deubiquitinates TRAF6 and TRAF2 proteins; our results prove that USP4 targets TRAF6 for K48 linked deubiquitination.
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USP4 targets TRAF6 through its USP domain.
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Recently, Xiao et al reported that USP4 targeted TRAF2 and TRAF6 for deubiquitination and inhibited the migration of tumor necrosis factor-alpha (TNF-alpha)-stimulated cancer cells.
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However, in breast cancer, USP4 was also recognized as a tumour suppressor for its up-regulatory effect on programmed cell death 4 (PDCD4) to restrain tumour growth.20 Moreover, USP4 was able to target TRAF2 and TRAF6 for deubiquitination and thereafter inhibited TNFalpha induced cancer cell migration.34 In the present study, we proved that USP4 expression was drastically increased in melanoma.
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USP4 activates ubiquitinated TRAF6. 1 / 1
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USP4 specifically targets ubiquitinated TRAF6 and then cleaves the polyubiquitin chains.
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USP4 inhibits TRAF6.
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USP4 inhibits TRAF6. 3 / 3
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Overexpression of USP4 inhibits EV71 replication by stabilizing TRAF6 to activate NF-kappaB inflammatory signaling.
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USP4 (ubiquitin specific peptidase 4) also negatively regulates TRAF6, by a mechanism that involves removal of polyubiquitin chains.
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55 Ubiquitin specific peptidase 4 (USP4) negatively regulates TRAF6, suppressing IL-1beta-induced NF-kappaB activation by removing polyubiquitin chains on TRAF6 in a deubiquitin activity dependent manner.
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USP4 decreases the amount of TRAF6.
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USP4 decreases the amount of TRAF6. 1 / 1
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USP4 silencing in LPS induced activation of microglia promoted the expression of p-p65 and TRAF6 and the secretion of TNF-alpha and IL-1beta.
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USP4 affects USP4
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USP4 activates USP4.
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USP4 activates USP4. 4 / 6
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Ubiquitination of USP4 could physically block its interaction with CtIP or induce conformational change of USP4.
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Ectopic expression of sh-RNA-resistant USP4 reverses the effect of USP4 knockdown.
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Together, these findings provided support for USP4 interactions with CtIP and MRN being critical for its DDR functions and for a model wherein USP4 auto-deubiquitylation promotes these interactions and thereby USP4 functions in DSB repair.
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Furthermore, gastrodin significantly upregulated the expression of USP4 and increased the binding of USP4 to the insulin receptor.Considering the importance of the PI3K-Akt pathway in the pathogenesis of T2DM, we detected the effects of gastrodin on the PI3K-Akt pathway to further explore the underlying mechanism of gastrodin in ameliorating insulin resistance.
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USP4 increases the amount of USP4.
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USP4 increases the amount of USP4. 2 / 2
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Specific inhibitory siRNA of USP4 reduced USP4 level and the parameters mentioned above.
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By inhibiting the expression of USP4, down-regulation of USP4 inhibited the proliferation, migration, and apoptosis of hypertrophic scar fibroblasts through the TGF-beta and Smad7 signaling pathway.
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USP4 decreases the amount of USP4.
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USP4 decreases the amount of USP4. 1 / 1
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Transient transfection of USP4 siRNA effectively reduced the expression of USP4 protein (XREF_FIG).
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USP4 affects TNF
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USP4 inhibits TNF.
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USP4 inhibits TNF. 4 / 6
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Moreover, we found that USP4 targets HDAC2 to downregulate tumor necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation.
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USP4 was identified by studies to negatively regulate both TNF-αand IL-1β-induced NF-κB activation [60] [61] [62] .
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USP4 negatively regulates TNFalpha induced, K63 linked TAK1 polyubiquitination and TAK1 mediated IKK and NF-kappaB activation [XREF_BIBR].
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USP4 was identified by studies to negatively regulate both TNF-alpha- and IL-1beta-induced NF-kappaB activation [XREF_BIBR, XREF_BIBR, XREF_BIBR].
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USP4 activates TNF.
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USP4 activates TNF. 1 / 2
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Ubiquitin specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFalpha induced cancer cell migration.
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TNF affects USP4
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TNF activates USP4.
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TNF activates USP4. 6 / 7
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To further determine the molecular interaction of USP4 and TAK1 in TNFalpha induced signal transduction, we overexpressed expression vector encoding MYC-USP4 in HEK-293T cells and treated with TNFalpha for the time points as indicated (XREF_FIG).
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These results suggest that TNFalpha induces association of USP4 with TAK1.
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We found that TNFalpha induced co-immunoprecipitation of MYC-USP4 and TAK1 as well as IKKbeta and RIPK1 within 10 min of stimulation (XREF_FIG).
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It was shown that TNFalpha induces the association of USP4 with TAK1 and deubiquitylation of K63 linked ubiquitin chains from TAK1, leading to the inhibition of NF-kappaB production.
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To determine whether USP4 inhibits TNFalpha induced TAK1 polyubiquitination, we overexpressed MYC-USP4-WT and -C311A mutant with HA-Ub in HEK293T cells and treated with TNFalpha for the time points indicated.
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Consistently, we also found that TNFalpha induced co-immunoprecipitation of endogenous USP4 and TAK1 as well as IKKbeta and RIPK1 (XREF_FIG).
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TNF inhibits USP4.
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TNF inhibits USP4. 1 / 1
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To determine the role of USP4 in the regulation of TNFalpha induced IL-6 gene expression, we extracted total RNAs from the control and USP4 knockdown HeLa cell lines treated with TNFalpha for the time points indicated and performed quantitative RT-PCR to examine the effect of USP4 knockdown on TNFalpha induced IL-6 expression.
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USP4 affects Wnt
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USP4 activates Wnt.
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USP4 activates Wnt. 4 / 5
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In addition to these newly identified nuclear functions, both USP4 and USP15 are well known to function in the cytosol, i.e. USP4 modulates the Wnt and beta-catenin, NF-kappaB, p53 and TGF-beta signaling pathways while USP15 performs functions in the TGF-beta receptor and NF-kappaB signaling pathways.
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However, in contrast to the previous work RNAi depletion of USP4 caused an up-regulation of Wnt signalling.
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However , later studies demonstrated that USP4 enhanced Wnt signaling through stabilizing and facilitating nuclear localization of beta-catenin , especially in cancer ( Yun et al ., 2015 ; Hwang et al ., 2016 ) .
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However, later studies demonstrated that USP4 enhanced Wnt signaling through stabilizing and facilitating nuclear localization of beta-catenin, especially in cancer.
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USP4 inhibits Wnt.
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USP4 inhibits Wnt. 2 / 2
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In this study, we found ubiquitin specific peptidase 4 (USP4) to strongly inhibit the Wnt and beta-catenin signaling by removing Lysine 63 linked poly-ubiquitin chain from Dishevelled (Dvl).
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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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USP4 increases the amount of Wnt.
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USP4 increases the amount of Wnt. 1 / 1
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Accordingly, USP4 significantly enhanced the expression of the WNT and beta-catenin downstream target genes, Cyclin D1 and Axin2.
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USP4 affects Ubiquitin
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USP4 activates Ubiquitin.
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USP4 activates Ubiquitin. 4 / 5
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Like other USPs, USP4 also mediates the removal and processing of ubiquitin.
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USP4 DUSP-Ubl promotes ubiquitin release.
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The DUSP-Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange.
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Pulse-chase analysis of Y-betagal degradation in yeast revealed that Y-betagal is degraded at wild-type rates when Unp is expressed (results not shown), consistent with the ONPG assay and reinforcing [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP4 inhibits Ubiquitin.
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USP4 inhibits Ubiquitin. 1 / 2
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Mutation of the conserved Cys residue of Unp to Ala (UnpC311A-FLAG and UnpDelta1-168 : C311A, Fig. 2, lanes 5 and 7) abolished the ubiquitin cleaving activity of Unp, as did the mutation of both conse[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP4 affects CDH1
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USP4 inhibits CDH1.
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USP4 inhibits CDH1. 3 / 3
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Neither transient nor stable overexpression of USP4 inhibited E-cadherin in Huh7 cells (Figure xref ).
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Through the immunoblotting analysis, we found that the knockdown of USP4 induced drastic down-regulation of N-cadherin and up-regulation of E-cadherin, indicating that USP4 deficiency could reverse the process of EMT.
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Neither transient nor stable overexpression of USP4 inhibited E-cadherin in Huh7 cells.
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USP4 decreases the amount of CDH1.
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USP4 decreases the amount of CDH1. 3 / 3
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In line with previous studies, we also showed that USP4 promoted melanoma metastasis by suppressing E-cadherin expression and increasing N-cadherin expression, indicating the ubiquitous existence of the crosstalk between USP4 and EMT in different kinds of cancer.
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Importantly, depressed expression of USP4 inhibited TβRI expression and partially reversed EMT stimulated by TGF-β1.In the meantime, blunted phosphorylation of Akt promoted the E-cadherin expression, and inhibited α-SMA and Vimentin expression in response to TGF-β1.
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We found that knockdown of both USP4 and beta-catenin downregulated the expression of ZEB1 and thereby increased the level of E-cadherin, indicating that the USP4 and beta-catenin axis is required for the EMT process and involves the regulation of ZEB1.
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USP4 increases the amount of CDH1.
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USP4 increases the amount of CDH1. 1 / 1
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Moreover, we performed RT-PCR experiment, and it also showed that the knockdown of USP4 could significantly decrease N-cadherin and increase E-cadherin expression at the transcriptional level.
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USP4 inhibits cell differentiation.
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USP4 inhibits cell differentiation. 4 / 4
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We observed that the activity and protein levels of both HDAC1 and HDAC4 are decreased when myoblast differentiation is promoted by the USP4 knockdown.
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Ubiquitin specific protease 4 (USP4) suppresses myoblast differentiation by down regulating MyoD activity in a catalytic independent manner.
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USP4 suppresses Wnt3a induced osteoblast differentiation and mineralization by cleaving K63 linked polyubiquitin chains from disheveled (Dvl) and inhibiting the accumulation of beta-catenin and activation of its downstream cascades.
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Naive CD4 + T cells were sorted using flow cytometry based analysis and were induced for Th2 cell differentiation, and were treated with the inhibitor of USP4, vialinin A, and then processed by flow cytometry.
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19 A recent study has demonstrated that USP4 could promote osteoblast differentiation via Activation of Wnt and beta-catenin signalling by inducing Runx2.
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Conversely, deubiquitination of the K48 linked polyubiquitination of RORgammat by the deubiquitinase ubiquitinspecific protease USP4 stabilizes RORgammat and promotes its activation of Th17 associated genes, whereas inhibition of USP4 activity diminishes Th17 differentiation.
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USP4 affects PDCD4
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USP4 activates PDCD4.
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USP4 activates PDCD4. 3 / 3
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In addition, proteasome inhibition by the addition of MG132 induced a significant increase in the PDCD4 expression level (XREF_FIG), suggesting that USP4 inhibits PDCD4 degradation.
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To determine whether PDCD4 is involved in the anti-proliferative function of USP4, we further examined the role of PDCD4 in the USP4 induced inhibition of proliferation by knocking down PDCD4 using siRNA.
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The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation.
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USP4 increases the amount of PDCD4.
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USP4 increases the amount of PDCD4. 2 / 2
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Furthermore, the knockdown of USP4 significantly decreased the endogenous PDCD4 protein expression level (XREF_FIG).
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USP4 upregulates PDCD4 expression in breast cancer cells.
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Modified USP4 increases the amount of PDCD4. 1 / 1
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The results revealed that the PDCD4 protein expression levels were significantly increased by USP4 ectopic expression in the BT549 cells and were significantly decreased by USP4 knockdown in the MCF7 cells (XREF_FIG).
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METTL3 affects USP4
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METTL3 decreases the amount of USP4.
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METTL3 decreases the amount of USP4. 4 / 4
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Given the key role of m 6 A mRNA methylation in affecting mRNA stability, it was reasonable to speculate that METTL3 knockdown reduces the m 6 A modification levels in USP4 mRNA and thus increase USP4 mRNA levels by atenuating the inhibitory effect of m 6 A modification on USP4 mRNA stability.
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Moreover, USP4 promoter transcriptional activity was not affected upon METTL3 knockdown, excluding the possibility that METTL3 downregulation inhibited USP4 transcription.
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And thus, we chose USP4, USP8, USP11, USP25 and USP28 for further analyses, and western blotting revealled that METTL3 knockdown markedly increased USP4 protein levels.
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We next found that METTL3 knockdown significantly upregulated USP4 mRNA levels in PCa cells.
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METTL3 inhibits USP4.
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METTL3 inhibits USP4. 1 / 1
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As predicted, we found that METTL3 overexpression induced ARHGDIA expression, but downregulated ELAVL1 and USP4 (XREF_SUPPLEMENTARY).
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METTL3 increases the amount of USP4.
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METTL3 increases the amount of USP4. 1 / 1
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METTL3 induces degradation of ELAVL1 protein by reducing USP4 protein levels.
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USP4 affects ODC1
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USP4 activates ODC1. 5 / 5
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It is worth noting that the activation of ODC by GNP or UNP decreases as the number of the phosphates, from triphos- phates to monophosphates, decrease.
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It is worth noting that the activation of ODC by GNP or UNP decreases as the number of the phosphates, from triphos- phates to monophosphates, decrease.
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Another interesting observation is that, whereas the native E. coli ODC is activated by many nucleotides [4], the recombinant, over- produced E. coli ODC is activated only by GNP or UNP.
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Another interesting observation is that, whereas the native E. coli ODC is activated by many nucleotides [4], the recombinant, over- produced E. coli ODC is activated only by GNP or UNP.
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Another interesting observation is that, whereas the native E. coli ODC is activated by many nucleotides [4], the recombinant, over- produced E. coli ODC is activated only by GNP or UNP.
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USP4 affects DNA repair
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USP4 activates DNA repair. 3 / 5
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Next, we examined how USP4 promotes DNA repair using well established reporter assays for HR and NHEJ (Bennardo et al., 2008; Fattah et al., 2010; Moynahan et al., 2001).
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USP4 depletion also sensitized cells to ionizing radiation (IR) (XREF_FIG E; see XREF_SUPPLEMENTARY D for depletion of the NHEJ protein XRCC4), providing additional evidence that USP4 promotes DNA repair.
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Here, we establish that the deubiquitylating enzyme USP4 promotes DNA-end resection and DNA repair by homologous recombination.
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USP4 affects inflammatory response
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USP4 inhibits inflammatory response.
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USP4 inhibits inflammatory response. 3 / 3
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Additionally, USP4 overexpression inhibited hepatocyte inflammation and apoptosis on hepatic I/R stimulation.
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In conclusion, USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver.
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In conclusion , USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver .
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USP4 activates inflammatory response.
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In experimental animal, there were increases in inflammation and fibrosis as well as USP4, and which were reduced after treatment of Vialinin A. Vialinin A also reduced Rheb and phosphorylated mTOR.
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Here the downregulation of USP4 promotes microglial activation and subsequent neuronal inflammation through attenuating the deubiquitination of K63 linked TRAF6 and reversing its suppressor role in the NF-kappaB signaling pathway.
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USP4 activates homologous recombination.
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USP4 was found to enhance DNA double-strand breaks repairment , DNA-end resection and homologous recombination via a conversed and specific domain to form a complex with CtIP and the MRE11-RAD50-NBS1 complex which can be abrogated by USP4 auto-deubiquitination on several specific cysteine residues .
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USP4 promotes DNA-end resection and HR by recruiting CtIP to DSB sites [94,95].
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USP4 auto-deubiquitination stabilizes its interaction with CtIP and MRN complex and stimulates HR repair [151,152].
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So far, however, we only have a relatively limited understanding of the DDR roles for deubiquitylation enzymes (DUBs), which mediate the processing of DNA end resection.In this study, we show that the[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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We also show that USP4 depletion impairs HR repair by affecting the process of DNA-end resection.
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USP4 affects cell growth
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USP4 inhibits cell growth.
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USP4 inhibits cell growth. 3 / 3
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Previous studies have shown that USP4 expression was significantly decreased in breast cancer tissue and that USP4 inhibited breast cancer cell growth through inhibiting PDCD4 degradation. xref USP4 was downregulated in lung adenocarcinoma and served as an independent predictor. xref Some other studies claimed that USP4 might have oncogenic properties.
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These results suggest that USP4 inhibits breast cancer cell growth and proliferation in vivo.
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Studies have reported that USP4 could inhibit breast cancer cell growth by upregulating PDCD4 [ xref ].
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USP4 activates cell growth.
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USP4 activates cell growth. 2 / 2
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The inhibition of USP4 in vitro significantly enhanced breast cancer cell growth and proliferation, while the overexpression of USP4 inhibited cell growth and proliferation.
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Using in vitro and in vivo assays, we demonstrated that USP4 overexpression enhanced HCC cell growth, migration, and invasion.
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USP4 affects TGFBR1
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USP4 activates TGFBR1.
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USP4 activates TGFBR1. 4 / 4
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Published studies revealed that , unlike USP15 , USP4 directly binds , stabilizes , and activates TbetaRI in the plasma membrane rather than via SMAD7-mediated recruitment to the active receptor as USP15 does .
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Therefore, USP4 mediates TbetaRI regulation via PI3K and Akt pathway, which is a strong modulator of TGF-beta pathway and plays a critical role in the crosstalk between TGF-beta and AKT signaling.
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As we have discussed above, USP4 can target the TGF-beta type I receptor and promote invasion and metastasis of breast cancer and high USP15 expression correlated with enhanced pSmad2 expression in ti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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In particular, USP4 pre-activates and/or persistently increases TbetaRI stabilization.
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USP4 increases the amount of TGFBR1.
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USP4 increases the amount of TGFBR1. 1 / 1
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Results showed that inhibition of USP4 and Smurf2 expression significantly reverses the altered expression of ZO-1, Vimentin and TbetaRI induced by TGF-beta1, while overexpression of Akt augments these effects.
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USP4 affects DDX58
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USP4 activates DDX58.
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USP4 activates DDX58. 3 / 3
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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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USP4 remove the K48-linked ubiquitination of RIG-I and promotes RIG-I signaling.
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USP4 remove the K48-linked ubiquitination of RIG-I and promotes RIG-I signaling .
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USP4 increases the amount of DDX58.
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Modified USP4 increases the amount of DDX58. 1 / 1
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Additionally, overexpression of USP4 dramatically enhanced the RIG-I protein level, while knockdown of USP4 had an opposite effect.
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USP4 increases the amount of DDX58. 1 / 1
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Additionally, overexpression of USP4 dramatically enhanced the RIG-I protein level, while knockdown of USP4 had an opposite effect.
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USP4 affects TRAF2
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USP4 activates TRAF2. 4 / 4
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Recently, Xiao et al reported that USP4 targeted TRAF2 and TRAF6 for deubiquitination and inhibited the migration of tumor necrosis factor-alpha (TNF-alpha)-stimulated cancer cells.
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USP4 has also been shown to target TRAF2 and TRAF6 inhibiting nuclear factor-kappaB (NF-kB) signalling and antagonizing lung cancer cell migration XREF_BIBR XREF_BIBR XREF_BIBR, suggesting a context dependent role in cancer.
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However, in breast cancer, USP4 was also recognized as a tumour suppressor for its up-regulatory effect on programmed cell death 4 (PDCD4) to restrain tumour growth.20 Moreover, USP4 was able to target TRAF2 and TRAF6 for deubiquitination and thereafter inhibited TNFalpha induced cancer cell migration.34 In the present study, we proved that USP4 expression was drastically increased in melanoma.
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USP4 has previously been confirmed to target TRAF2 and TRAF6 for deubiquitination and it has been established that USP4 inhibits TNFalpha induced cancer cell migration 35.
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USP4 affects TGFB1
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USP4 activates TGFB1. 3 / 4
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Further studies demonstrated that USP4 mediated TGF-beta1 activation not only enhances the phosphorylation of Smad2 through TGF-beta, but also directly upregulate matrix metalloproteinase (MMP)-9-mediated cell migration and invasion of breast cancer cells.
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Western blot analyses showed that the TbetaR-1 expression was significantly increased in HPMCs treated with TGF-beta1 and Flag-Akt, whereas no change was seen in cells treated with Smurf2 siRNA or USP4 siRNA.
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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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MAP3K7 affects USP4
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MAP3K7 activates USP4. 4 / 4
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Previous study also showed that USP4 targets TAK1 by removing K63 linked polyubiquitination and then recruit IkappaB kinase (IKK) complex to simulate TNF-alpha -induced NF-kappaB activation 49.
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TAK1 was required for USP4 function in hepatic I/R injury as TAK1 inhibition abolished USP4 function in vitro In conclusion, our study demonstrates that USP4 deficiency plays a detrimental role in hepatic I/R injury by promoting activation of the TAK1 and JNK signalling pathways.
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Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor beta activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo.
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USP4 binds to overexpressed TAK1 with TAB1 and TNFalpha induces association of USP4 with TAK1.
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Gastrodin affects USP4
| 4
Gastrodin increases the amount of USP4. 4 / 4
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Our results indicate that gastrodin promotes the phosphorylation of GATA1 via the PI3K/AKT pathway, enhances the transcriptional activity of GATA1, and then increases the expression level of USP4, thereby reducing the ubiquitination and degradation of insulin receptors and ultimately improving insulin resistance.
| PMC
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Compared to the IR group, gastrodin upregulated the ratio of p-Akt/total Akt by 50.09, 153.81, and 155.27% and upregulated USP4 expression by 15.66, 84.50, and 143.24% at 10, 30, and 100 μg/ml, respectively.
| PMC
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Furthermore, gastrodin significantly upregulated the expression of USP4 and increased the binding of USP4 to the insulin receptor.Considering the importance of the PI3K-Akt pathway in the pathogenesis of T2DM, we detected the effects of gastrodin on the PI3K-Akt pathway to further explore the underlying mechanism of gastrodin in ameliorating insulin resistance.
| PMC
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Thus, these results indicate that gastrodin promotes the phosphorylation of GATA1 and upregulate its transcriptional activity via the PI3K-Akt pathway, promotes USP4 gene transcription, and upregulates USP4 expression.
| PMC
USP4 activates epithelial to mesenchymal transition. 3 / 3
| 1 2
eidos
Recently , USP4 was found to mediate deubiquitination of the epithelial-mesenchymal transition ( EMT ) transcriptional factor Twist1 to promote lung cancer cell stemness ( Li et al ., 2020 ) .
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3.4 USP4 up-regulation contributes to melanoma invasion and migration by promoting EMT.
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Collectively, these data demonstrated that USP4 promotes melanoma cell migration and invasion by promoting EMT.
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Through the immunoblotting analysis, we found that the knockdown of USP4 induced drastic down-regulation of N-cadherin and up-regulation of E-cadherin, indicating that USP4 deficiency could reverse the process of EMT.
29542252
USP4 affects USP15
| 3
USP4 activates USP15.
| 2
USP4 activates USP15. 2 / 3
| 2
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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.
| 1
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.
23105109
USP4 affects ERK
| 4
USP4 increases the amount of ERK.
| 2
USP4 increases the amount of phosphorylated ERK. 2 / 2
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TGF-betaR inhibition reduced level of TGF-betaR1, p-smad2 and p-ERK1/2 which can partially be rescued by USP4 overexpression.
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Inhibition of USP4 downregulated the expression of PCNA, Bcl-2 and p-ERK1/2, but upregulated the expression of Bax both in vitro and in vivo.
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USP4 activates ERK.
| 2
USP4 activates ERK. 2 / 2
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Zhou et al. found that USP4, as a potential novel oncogene, promotes Glioblastoma multiforme (GBM) by activating the ERK pathway through TGF-beta regulation [XREF_BIBR].
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XREF_BIBR also demonstrated that inhibiting USP4 expression in GBM cells both inhibited their proliferation and induced apoptosis via antagonizing USP4 mediated stimulation of the ERK signaling pathway.
33681193
SART3 affects USP4
| 2
SART3 inhibits USP4.
| 1
SART3 inhibits USP4. 1 / 2
| 1
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The complex structure of SART3 nuclear localization signal (NLS) and importin-alpha reveals bipartite binding, and removal of SART3 NLS prevents the entry of USP4 (and USP15) into the nucleus and abrogates the subsequent deubiquitinase activity of USP4.
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SART3 activates USP4.
| 1
SART3 activates USP4. 1 / 2
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While it has been reported that overexpressed SART3 causes nuclear localization of exogenously expressed USP4, we found that SART3 depletion from U2OS cells did not detectably affect the nuclear and cytoplasmic distribution of endogenous USP4 (data not shown), suggesting that USP4 nuclear targeting might be mediated by multiple mechanisms.
26455393
AKT affects USP4
| 4
AKT activates USP4.
| 3
AKT activates USP4. 3 / 3
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Based on this study, it would be interesting to investigate whether USP4 function, which is also modulated by AKT as described above, is also affected in CYLD knockout mice XREF_BIBR.
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This study suggests that Akt activation in breast cancer cells induces USP4 to relocate and stabilize TbetaRI in the plasma membrane, and thereby enforces TGF-beta-induced pro tumorigenic responses.
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According to a previous study by Iyengar [XREF_BIBR], Akt promotes USP4 to enter the cell membrane and cytoplasm to phosphorylate USP4 and regulate its subcellular localization, and Akt phosphorylation of USP4 occurs by combining with other de-ubiquitinating enzymes (DUBs) to de-ubiquitinate the TGF-beta receptor [XREF_BIBR].
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AKT increases the amount of USP4.
| 1
AKT increases the amount of USP4. 1 / 1
| 1
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Therefore, these results suggest that gastrodin stimulates the PI3K/AKT pathway and that activation of the PI3K/AKT pathway promotes USP4 expression by enhancing the phosphorylation of GATA1 in HepG2 cells.
| PMC
USP4 affects ZEB1
| 4
USP4 increases the amount of ZEB1.
| 3
USP4 increases the amount of ZEB1. 2 / 2
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We found that knockdown of both USP4 and beta-catenin downregulated the expression of ZEB1 and thereby increased the level of E-cadherin, indicating that the USP4 and beta-catenin axis is required for the EMT process and involves the regulation of ZEB1.
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In the present study, we found that the USP4 and beta-catenin axis was involved in metastatic potential through USP4 mediated stabilization of beta-catenin and that knockdown of USP4 and beta-catenin suppressed the metastatic potential including clonogenicity, migration, and invasion, and induced MET by downregulating ZEB1 expression.
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Modified USP4 increases the amount of ZEB1. 1 / 1
| 1
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USP4 overexpression increased ZEB1 expression and accordingly, the expression level of E-cadherin was decreased.
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USP4 inhibits ZEB1.
| 1
USP4 inhibits ZEB1. 1 / 1
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Moreover, knockdown of both USP4 and beta-catenin inhibited clonogenicity and induced mesenchymal-epithelial transition by downregulating ZEB1 in PC14PE6 and LvBr4 cells.
26883469
USP4 affects ELAVL1
| 1 3
USP4 activates ELAVL1.
| 1 1
USP4 activates ELAVL1. 2 / 2
| 1 1
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Taken together , our results demonstrated that USP4 upregulates ELAVL1 expression by removing the ubiquitin group from ELAVL1 protein .
| PMC
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Consistently, USP4 knockdown markedly reduced protein stability of ELAVL1.
| PMC
USP4 increases the amount of ELAVL1.
| 1
USP4 increases the amount of ELAVL1. 1 / 1
| 1
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Taken together, our results demonstrated that USP4 upregulates ELAVL1 expression by removing the ubiquitin group from ELAVL1 protein.
| PMC
USP4 decreases the amount of ELAVL1.
| 1
USP4 decreases the amount of ELAVL1. 1 / 1
| 1
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Additionally, the overexpression of USP4 effectively decreased the ubiquitination levels of ELAVL1.
| PMC
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It was also found that USP4 inhibited NF-kappaB activation, but in this study we confirmed that USP4 positively regulates the NF-kappaB signalling pathway during EV71 infection.
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The hypothesis that drove this study was that USP4 might also mediate the TGF-beta signal transduction pathway in hypertrophic scar fibroblasts.
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As shown in previous studies [XREF_BIBR], USP4 is an effective inducer of TGF-beta signal transduction, which interacts directly with TGF-betaR1 and acts as a de-ubiquitinase enzyme to maintain the level of TGF-betaR1 on the plasma membrane.
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USP4 affects Ubiquitination
| 3
USP4 inhibits Ubiquitination. 3 / 3
| 3
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Inhibition of USP4 significantly produced ubiquitination level of Rheb in immunoprecipitated solution , although same amount of Rheb and USP4 proteins were loaded to immunoprecipitation solution ( Figure 6C ) .
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17 However , USP4 as an deubiquitinating enzymes reverses the ubiquitination .
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When substrate is not present RHO52 may auto-ubiquitinate itself and USP4 reverses this ubiquitination .
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USP4 affects AKT
| 3
USP4 activates AKT. 3 / 3
| 3
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AKT regulation of mesothelial-to-mesenchymal transition in peritoneal dialysis is modulated by smurf2 and deubiquitinating enzyme USP4.
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These data implied that Akt mediated MMT in PD via Smurf2 modulation and and or Smad7 degradation while conceivably maintaining the TbetaRI stability, most likely by the USP4.
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The deubiquitinating enzyme USP4 modulates AKT regulation of mesothelial-to-mesenchymal transition in peritoneal dialysis (Xiao et al., 2015).
| PMC
USP15 affects USP4
| 2
USP15 activates USP4. 2 / 3
| 2
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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.
28088760
USP4 affects VIM
| 3
USP4 increases the amount of VIM.
| 2
USP4 increases the amount of VIM. 2 / 2
| 2
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Results showed that inhibition of USP4 and Smurf2 expression significantly reverses the altered expression of ZO-1, Vimentin and TbetaRI induced by TGF-beta1, while overexpression of Akt augments these effects.
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Importantly, depressed expression of USP4 inhibited TβRI expression and partially reversed EMT stimulated by TGF-β1.In the meantime, blunted phosphorylation of Akt promoted the E-cadherin expression, and inhibited α-SMA and Vimentin expression in response to TGF-β1.
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USP4 decreases the amount of VIM.
| 1
USP4 decreases the amount of VIM. 1 / 1
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In addition, inhibition of Ubiquitin carboxyl-terminal hydrolase 4 (USP4) decreased TGF- beta1 induced expression of TbetaR-I and reversed the altered expression of Smad7, Smurf2, ZO-1 and Vimentin.
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USP4 affects SMAD7
| 3
USP4 decreases the amount of SMAD7.
| 2
USP4 decreases the amount of SMAD7. 2 / 2
| 2
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Also, detection of the expression levels of TGF-betaR1and Smad7 proteins showed that the down-regulation of USP4 inhibited the expression of TGF-betaR1 and promoted the expression of Smad7.
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In addition, inhibition of Ubiquitin carboxyl-terminal hydrolase 4 (USP4) decreased TGF- beta1 induced expression of TbetaR-I and reversed the altered expression of Smad7, Smurf2, ZO-1 and Vimentin.
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USP4 increases the amount of SMAD7.
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USP4 increases the amount of SMAD7. 1 / 1
| 1
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Also, detection of the expression levels of TGF-betaR1and Smad7 proteins showed that the down-regulation of USP4 inhibited the expression of TGF-betaR1 and promoted the expression of Smad7.
32308208
USP4 affects RPS4X
| 3
USP4 inhibits RPS4X.
| 2
USP4 inhibits RPS4X. 2 / 2
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The findings showed that the expression of TGF-betaR1 and USP4 were increased in hypertrophic scar tissues and fibroblasts, and that down-regulating USP4 inhibited hypertrophic scar fibroblast proliferation and migration and induced cell apoptosis in vitro.
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The Cell Counting Kit-8 (CCK-8) assay results showed that the proliferation of hypertrophic scar fibroblasts transfected with siUSP4 was significantly inhibited on the fifth and seventh day, indicating that down-regulation of USP4 could suppress the proliferation of hypertrophic scar fibroblasts.
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USP4 activates RPS4X.
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USP4 activates RPS4X. 1 / 1
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The hypothesis that drove this study was that USP4 might also mediate the TGF-beta signal transduction pathway in hypertrophic scar fibroblasts.
32308208
USP4 affects METTL3
| 3
USP4 inhibits METTL3.
| 2
USP4 inhibits METTL3. 2 / 2
| 2
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Moreover , we observed that USP4 knockdown effectively alleviated METTL3 knockdown-induced inhibited xenograft tumor growth ( Figure 7A-C ) .
| PMC
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Moreover , we also found that the knockdown of USP4 effectively alleviated METTL3 decifiency-induced suppressed xenograft tumor formation .
| PMC
USP4 activates METTL3.
| 1
USP4 activates METTL3. 1 / 1
| 1
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Moreover , METTL3 silencing dramatically suppressed lung metastatic abilities of PC3 cells , as evidenced by the number of lung metastatic nodules ( Figure 7D-F ) ; however , the knockdown of USP4 effectively attenuated METTL3 deficiency - induced decreased lung metastatic capacity of PC3 cells ( Figure 7D-F ) .
| PMC
USP4 affects IRF4
| 3
USP4 activates IRF4.
| 2
USP4 bound to IRF4 activates IRF4. 2 / 2
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On the whole, our data indicate that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be related to the pathological process of RHD.
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To conclude, this study indicated that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be associated with the pathological process of RHD.
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USP4 increases the amount of IRF4.
| 1
USP4 increases the amount of IRF4. 1 / 1
| 1
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USP4 knockdown not only decreased the expression level of IRF4, but also affected the expression level of Th2 related cytokines.
28791349
USP4 affects IL1B
| 2 1
USP4 inhibits IL1B.
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USP4 inhibits IL1B. 2 / 2
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Similarly, USP4 inhibited IL-1β-, LPS- and TGFβ-induced NF-κB production xref .
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USP4 inhibits IL-1β-, LPS-and TGFβ-induced NF-κB activation.
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USP4 activates IL1B.
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USP4 activates IL1B. 1 / 1
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Knockdown of USP4 promoted IL-1beta, LPS, and TGF-beta-induced NF-kappaB activation (Fan et al., 2011).
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USP4 affects Cell Survival
| 1 2
USP4 activates Cell Survival.
| 1 1
USP4 activates Cell Survival. 2 / 2
| 1 1
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Similarly, knockdown of USP4 significantly decreases cell viability in a p53 dependent manner after treating GMB cells with temozolomide.
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Similarly , knockdown of USP4 significantly decreases cell viability in a p53-dependent manner after treating GMB cells with temozolomide ( Qin et al ., 2019 ) .
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USP4 inhibits Cell Survival.
| 1
USP4 inhibits Cell Survival. 1 / 1
| 1
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USP4 depletion did not inhibit cell survival in the absence of DNA damage.
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USP4 affects CDH2
| 3
USP4 increases the amount of CDH2.
| 2
USP4 increases the amount of CDH2. 2 / 2
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In line with previous studies, we also showed that USP4 promoted melanoma metastasis by suppressing E-cadherin expression and increasing N-cadherin expression, indicating the ubiquitous existence of the crosstalk between USP4 and EMT in different kinds of cancer.
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Moreover, we performed RT-PCR experiment, and it also showed that the knockdown of USP4 could significantly decrease N-cadherin and increase E-cadherin expression at the transcriptional level.
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USP4 inhibits CDH2.
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USP4 inhibits CDH2. 1 / 1
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Through the immunoblotting analysis, we found that the knockdown of USP4 induced drastic down-regulation of N-cadherin and up-regulation of E-cadherin, indicating that USP4 deficiency could reverse the process of EMT.
29542252
USP4 affects PPIA
| 3
USP4 inhibits PPIA.
| 1
USP4 inhibits PPIA. 1 / 1
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In contrast, down-regulation of USP4 via shRNAs in MHCC97H cells significantly decreased endogenous CypA.
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USP4 increases the amount of PPIA.
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USP4 increases the amount of PPIA. 1 / 1
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Inhibition of USP4 by shRNA in MHCC97H cells significantly decreased CypA protein levels.
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USP4 activates PPIA.
| 1
USP4 activates PPIA. 1 / 1
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Western blotting showed that endogenous CypA protein was significantly increased by USP4 overexpression in a dose dependent manner.
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Torcetrapib affects USP4
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Torcetrapib increases the amount of USP4. 2 / 2
2 |
ctd
No evidence text available
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ctd
No evidence text available
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Sodium arsenite affects USP4
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Sodium arsenite increases the amount of USP4. 2 / 2
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ctd
No evidence text available
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ctd
No evidence text available
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Short hairpin RNA affects USP4
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Short hairpin RNA inhibits USP4. 2 / 2
| 2
sparser
Inhibition of USP4 by shRNA in MHCC97H cells significantly decreased CypA protein levels.
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In contrast, inhibition of USP4 by shRNA in MHCC97H cells reduced p-ERK1/2 and increased p-CrkII levels.
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Methyl methanesulfonate increases the amount of USP4. 2 / 2
2 |
ctd
No evidence text available
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ctd
No evidence text available
26011545
Benzo[a]pyrene affects USP4
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Benzo[a]pyrene increases the amount of USP4. 2 / 2
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ctd
No evidence text available
22228805
ctd
No evidence text available
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Ubiquitin affects USP4
| 2
Ubiquitin activates USP4. 2 / 2
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Pre-steady-state kinetics measurements reveal that USP4 catalytic domain activity is strongly inhibited by slow dissociation of ubiquitin after substrate hydrolysis.
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The Effects of the Transforming Growth Factor-beta1 (TGF-beta1) Signaling Pathway on Cell Proliferation and Cell Migration are Mediated by Ubiquitin Specific Protease 4 (USP4) in Hypertrophic Scar Tissue and Primary Fibroblast Cultures.
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USP4 affects hyaluronan
| 2
USP4 inhibits hyaluronan. 2 / 2
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The silencing of USP17 led to decreased hyaluronan production, whereas the suppression of USP4 increased hyaluronan synthesis.
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Knockdown of USP17 decreases, whereas knockdown of USP4 increases hyaluronan production.
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USP4 affects IRF8
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USP4 activates IRF8. 2 / 2
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Deconjugation of polyubiquitin chains from IRF8 mediated by USP4 is vital for maintaining the function of regulatory T cells, which negatively regulate many different immune reactions.
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USP4 interacts and positively regulates IRF8 function via K48 linked deubiquitination in regulatory T cells.
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USP4 affects IL1
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USP4 inhibits IL1. 2 / 2
| 2
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USP4 negatively regulates IL-1β-induced NF-κB activation [60] [61] [62] .
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USP4 was identified by studies to negatively regulate both TNF-αand IL-1β-induced NF-κB activation [60] [61] [62] .
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USP4 affects IFNB1
| 1 1
USP4 activates IFNB1. 2 / 2
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Thus, USP4 positively regulates IFN-beta signaling by interacting with the N-terminal domain of RIG-I, subsequently leading to the inhibition of RIG-I degradation.
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Similarly , in vesicular stomatitis virus ( VSV ) infection , removing K48-linked polyubiquitin chains from RIG-I allows USP4 to enhance RIG-I-triggered IFN-beta signaling , thereby inducing an antiviral immune response ( Wang et al ., 2013 ) .
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USP4 affects HUWE1
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USP4 inhibits HUWE1. 1 / 2
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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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So far, however, we only have a relatively limited understanding of the DDR roles for deubiquitylation enzymes (DUBs), which mediate the processing of DNA end resection.In this study, we show that the[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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These results suggest that USP4 promotes DSB repair by HR.HR is initiated by DNA end resection, which generates 3 ' ssDNA tails that are coated by RPA (Chen et al., 2013).
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USP4 affects Angiotensin-2
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USP4 inhibits Angiotensin-2. 2 / 2
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Adenovirus mediated gain- and loss-of-function approaches indicated that deficiency of endogenous USP4 promoted myocyte hypertrophy induced by angiotensin II in vitro, whereas restoration of USP4 significantly attenuated the prohypertrophic effect of angiotensin II.
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Overexpression of USP4 can prevent angiotensin II induced cardiac hypertrophy and fibrosis in vitro and ameliorate cardiac dysfunction in vivo through downregulation of the TAK1/JNK1/2/p38 signaling pathway.
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TRAF6 affects USP4
| 2
TRAF6 activates USP4. 2 / 2
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However, there is no evidence of how USP4 deubiquitinates TRAF6 and TRAF2 proteins; our results prove that USP4 targets TRAF6 for K48 linked deubiquitination.
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USP4 targets TRAF6 through its USP domain.
30194441
Ser-Leu affects USP4
| 2
Ser-Leu activates USP4. 2 / 2
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Mutations in the SL modulate USP4 activity.
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On the side of the catalytic domain, we found that mutation F386G in the SL region, near the catalytic site (XREF_FIG), substantially increases USP4 CD activity (XREF_FIG), in the absence of the DUSP-Ubl.
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PDCD4 affects USP4
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PDCD4 activates USP4. 2 / 2
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The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation.
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To examine this hypothesis, we first determined whether PDCD4 is a downstream target of USP4 in breast cancer cells.
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GPI affects USP4
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GPI activates USP4. 2 / 2
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Interestingly, NLK promoted nuclear accumulation USP4.
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Overexpression of a catalytically active Nlk promotes nuclear accumulation of USP4 whereas a subpopulation of TCF4 is a substrate of USP4 dependent deubiquitination.
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CNR2 affects USP4
| 2
CNR2 inhibits USP4. 2 / 2
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Conclusion : LXRalpha exerts a cytoprotective effect against TGF-beta by transcriptionally regulating the CB2 gene in hepatocytes, and CB2 then inhibits USP4 stabilizing TbetaRI through miR-27b.
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Thus, LXRalpha could exert a protective effect against TGF-beta by transcriptional regulation of the CB2R gene in hepatocytes, and then CB2 might inhibit USP4 stabilizing TbetaRI via miR-27b.
| PMC
Bisphenol A affects USP4
2 |
Bisphenol A increases the amount of USP4.
1 |
Bisphenol A increases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
30816183
Bisphenol A decreases the amount of USP4.
1 |
Bisphenol A decreases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
25181051
USP4 affects ecdysone
| 2
Mutated USP4 activates ecdysone. 1 / 1
| 1
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Activation of BrC-Z1 as well as EcR, itself an ecdysone response gene, can be mediated by both the USP3 and USP4 mutant proteins.
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USP4 activates ecdysone. 1 / 1
| 1
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USP3 and USP4 also activate an ecdysone responsive element, hsp27EcRE, in cultured cells.
11274407
USP4 affects TJP1
| 2
USP4 increases the amount of TJP1.
| 1
USP4 increases the amount of TJP1. 1 / 1
| 1
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Results showed that inhibition of USP4 and Smurf2 expression significantly reverses the altered expression of ZO-1, Vimentin and TbetaRI induced by TGF-beta1, while overexpression of Akt augments these effects.
25885904
USP4 decreases the amount of TJP1.
| 1
USP4 decreases the amount of TJP1. 1 / 1
| 1
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In addition, inhibition of Ubiquitin carboxyl-terminal hydrolase 4 (USP4) decreased TGF- beta1 induced expression of TbetaR-I and reversed the altered expression of Smad7, Smurf2, ZO-1 and Vimentin.
25885904
USP4 affects TGFBR
| 2
USP4 inhibits TGFBR.
| 1
USP4 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).
33335288
USP4 activates TGFBR.
| 1
USP4 activates TGFBR. 1 / 1
| 1
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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.
24399297
USP4 affects RBBP8
| 2
USP4 inhibits RBBP8.
| 1
USP4 inhibits RBBP8. 1 / 1
| 1
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Moreover, we found that USP4 depletion markedly impaired DNA-damage accumulation of the DNA-end resection factor CtIP.
26455393
USP4 activates RBBP8.
| 1
USP4 activates RBBP8. 1 / 1
| 1
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As shown in Figures 5 A-5D, WT USP4, but not the insert domain deletion mutant, restored CtIP and downstream RAD51 and RPA foci in USP4 depleted cells after IR.
26387952
USP4 affects INS
| 2
USP4 decreases the amount of INS.
| 1
USP4 decreases the amount of INS. 1 / 1
| 1
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Upregulation of USP4 reduces the ubiquitination and degradation of insulin receptors, upregulates the level of insulin receptors, and ultimately improves insulin resistance.
| PMC
USP4 activates INS.
| 1
USP4 activates INS. 1 / 1
| 1
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Furthermore, gastrodin significantly upregulated the expression of USP4 and increased the binding of USP4 to the insulin receptor.Considering the importance of the PI3K-Akt pathway in the pathogenesis of T2DM, we detected the effects of gastrodin on the PI3K-Akt pathway to further explore the underlying mechanism of gastrodin in ameliorating insulin resistance.
| PMC
USP4 affects FN1
| 2
USP4 decreases the amount of FN1.
| 1
USP4 decreases the amount of FN1. 1 / 1
| 1
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In addition, Smurf2 siRNA and USP4 siRNA reduced the up-regulated expression of FN in HPMCs induced by TGF-beta1plus Flag-Akt.
25885904
USP4 activates FN1.
| 1
USP4 activates FN1. 1 / 1
| 1
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No change in the FN expression was observed in cells treated with Smurf2 siRNA or USP4 siRNA alone compared to basal levels.
25885904
USP4 affects Aging
| 2
USP4 inhibits Aging.
| 1
USP4 inhibits Aging. 1 / 1
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Indeed, it has been suggested that Usp4 is a potential oncogene because it inhibits p53 activity, p53-associated apoptosis and cell-cycle checkpoints; depletion of USP4 promotes cell senescence; loss of USP4 inhibits oncogene-induced primary cell transformation, and finally USP4 is over-expressed in a subset of human cancers [86].
23712866
USP4 activates Aging.
| 1
USP4 activates Aging. 1 / 1
| 1
reach
Indeed, it has been suggested that Usp4 is a potential oncogene because it inhibits p53 activity, p53 associated apoptosis and cell-cycle checkpoints; depletion of USP4 promotes cell senescence; loss of USP4 inhibits oncogene induced primary cell transformation, and finally USP4 is over-expressed in a subset of human cancers [XREF_BIBR].
23712866
HDAC2 affects USP4
| 2
HDAC2 inhibits USP4.
| 1
HDAC2 inhibits USP4. 1 / 1
| 1
reach
Quantitative real-time RT-PCR analysis revealed that HDAC2 mRNA levels were unchanged after knockdown of USP4 (XREF_FIG).
26411366
HDAC2 activates USP4.
| 1
HDAC2 activates USP4. 1 / 1
| 1
reach
Moreover, we found that USP4 targets HDAC2 to downregulate tumor necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation.
26411366
Vinclozolin affects USP4
1 |
Vinclozolin decreases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
23034163
Valproic acid affects USP4
1 |
Valproic acid decreases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
23179753
Ubl affects USP4
| 1
Ubl inhibits USP4. 1 / 1
| 1
reach
To test whether the Ubl domain can inhibit the DUB activity of USP4, we repeated the in trans inhibition assay with USP4-D1D2 in the presence of increasing amounts of the Ubl domain (XREF_SUPPLEMENTARY online) and found that it provides inhibition equal to the insert.
21415856
Tris(1,3-dichloro-2-propyl)phosphate increases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
26179874
Titanium dioxide affects USP4
1 |
Titanium dioxide decreases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
29264374
Temozolomide affects USP4
| 1
Temozolomide activates USP4. 1 / 1
| 1
reach
In addition, the results revealed that cleaved poly (ADP-ribose) polymerase level increased when USP4 was knocked down in glioblastoma cells treated with TMZ.
30655854
Stop protein affects USP4
| 1
Stop protein inhibits USP4. 1 / 1
| 1
reach
To assess the effect of USP4 silencing on beta-catenin protein stability, transfected cells were treated with 40mug/ml cycloheximide to stop protein synthesis.
26883469
Sodium fluoride affects USP4
1 |
Sodium fluoride increases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
28918527
Selenium atom affects USP4
1 |
Selenium atom decreases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
19244175
Resveratrol affects USP4
1 |
Resveratrol increases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
12002526
Quercetin affects USP4
1 |
Quercetin decreases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
21632981
Pirinixic acid affects USP4
1 |
Pirinixic acid increases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
23811191
Phlorizin affects USP4
1 |
Phlorizin increases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
22538082
Pentachlorophenol affects USP4
1 |
Pentachlorophenol decreases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
24642059
Paracetamol affects USP4
1 |
Paracetamol decreases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
21420995
Menadione affects USP4
| 1
Menadione inhibits USP4. 1 / 1
| 1
reach
Effect of ATP on menadione inhibition of UNP stimulated ATPase.
14236650
Lipopolysaccharide affects USP4
| 1
Lipopolysaccharide decreases the amount of USP4. 1 / 1
| 1
reach
In vitro LPS induced activation of microglia showed decreased expression of USP4 and increased expression of p-p65 and TRAF6.
28755289
Hsa-miR-148a-3p affects USP4
1 |
Hsa-miR-148a-3p decreases the amount of USP4. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
24798342
Finasteride affects USP4
1 |
Finasteride increases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
24136188
Ellagic acid affects USP4
1 |
Ellagic acid decreases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
12002526
Decabromodiphenyl ether increases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
23640034
Cylindrospermopsin zwitterion increases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
24921660
Cyclosporin A affects USP4
1 |
Cyclosporin A increases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
25562108
Coumestrol affects USP4
1 |
Coumestrol decreases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
19167446
Bis(2-ethylhexyl) phthalate decreases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
31163220
Vitamin E affects USP4
1 |
Vitamin E decreases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
19244175
Ubx affects USP4
| 1
Ubx decreases the amount of USP4. 1 / 1
| 1
reach
Expression of unp in the founder cells for the cerebral branch within the first tracheal metamere is repressed in posterior segments by Ubx and other bithorax complex genes.
8582298
USP4 affects transport
| 1
USP4 activates transport. 1 / 1
| 1
reach
The assay results revealed that transcriptional activity increases in proportion to the amount of USP4 in the nucleus, which suggests that USP4 enhances beta-catenin activity by facilitating its trans[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
26189775
USP4 affects translocation
| 1
USP4 activates translocation. 1 / 1
| 1
eidos
It is possible that ALAL-1 induces conformational changes in SART3 / USP4 that promote their translocation , for which importin has been shown to be required ( Park et al ., 2016 ) .
32858747
USP4 bound to TCF4 inhibits transcription, DNA-templated. 1 / 1
| 1
reach
For example, USP4 interacts with and deubiquitinates TCF4, which inhibits beta-catenin-dependent transcription [XREF_BIBR].
33051403
USP4 affects relaxin
| 1
USP4 activates relaxin. 1 / 1
| 1
reach
By promoting activation of the relaxin and TGF-beta 1/Smad2/matrix metalloproteinase 9 axis and transcriptional repression activity of HDAC2, USP4 induces breast cell invasion, migration, and proliferation both in vitro and in vivo.
33681193
USP4 activates reactive oxygen species. 1 / 1
| 1
reach
In contrast to these observations with ANPs, although UNP and CNP triggered increased ROS, notably in AT2 and MAC, this did not impact on mitochondrial integrity or cell viability, indicating the significance of surface chemistry in cellular bioreactivity.
26133975
USP4 affects pkbA
| 1
USP4 activates pkbA. 1 / 1
| 1
reach
Western blot analyses showed that the TbetaR-1 expression was significantly increased in HPMCs treated with TGF-beta1 and Flag-Akt, whereas no change was seen in cells treated with Smurf2 siRNA or USP4 siRNA.
25885904
USP4 activates osteoblast differentiation. 1 / 1
| 1
eidos
19 A recent study has demonstrated that USP4 could promote osteoblast differentiation via Activation of Wnt / beta-catenin signalling by inducing Runx2 .
33434305
USP4 inhibits necrotic cell death. 1 / 1
| 1
reach
Moreover, we found that USP4 targets HDAC2 to downregulate tumor necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation.
26411366
USP4 affects lipopolysaccharide
| 1
reach
Knockdown of USP4 promoted IL-1beta, LPS, and TGF-beta-induced NF-kappaB activation (Fan et al., 2011).
27155333
USP4 activates interleukin-4 secretion. 1 / 1
| 1
eidos
In the study of rheumatic heart disease , Guo et al. revealed that USP4 positively modulated IL-4 secretion by T helper type 2 cells through deubiquitinating and stabilizing IRF4 which is usually the reason of allergic immune responses diseases , such as rheumatic heart disease [ 62 ] .
32669974
reach
For example, USP4 targets and deubiquitinates hyaluronan synthase 2 (HAS2), but USP4 does not maintain the stability of HAS, and, rather, loss of USP4 increases hyaluronan synthesis [33].
| PMC
USP4 activates defense response to virus. 1 / 1
| 1
reach
USP4 positively regulates the RIG-I-mediated antiviral response through the deubiquitination of Lys48-linked polyubiquitin from RIG-I43.
26061460
reach
56 Loss of USP4 enhances cytokine production mediated by LPS and IL-1beta.
23429360
eidos
Indeed , it has been suggested that Usp4 is a potential oncogene because it inhibits p53 activity , p53-associated apoptosis and cell-cycle checkpoints ; depletion of USP4 promotes cell senescence ; loss of USP4 inhibits oncogene-induced primary cell transformation , and finally USP4 is over-expressed in a subset of human cancers [ 86 ] .
23712866
USP4 affects cell death
| 1
USP4 activates cell death. 1 / 1
| 1
reach
Although UNP and CNP did not induce significant cell death, both these particles induced a high ROS response in AT2, similar to that observed following ANP exposure, but less so in TT1 cells, illustrating that induction of ROS varies according to the target cell.
26133975
USP4 affects cell cycle
| 1
USP4 activates cell cycle. 1 / 1
| 1
reach
Loss of Usp4 in cells interferes with the accumulation of correctly spliced mRNAs, including those for alpha-tubulin and Bub1, and impairs cell cycle progression.
20595234
USP4 affects biomineralization
| 1
eidos
USP4 suppresses Wnt3a-induced osteoblast differentiation and mineralization by cleaving K63-linked polyubiquitin chains from disheveled ( Dvl ) and inhibiting the accumulation of beta-catenin and activation of its downstream cascades ( Zhou et al ., 2016 ) .
33681193
USP4 affects VP1
| 1
Modified USP4 decreases the amount of VP1. 1 / 1
| 1
reach
In order to confirm the relationship between USP4 and EV71 infection, USP4 was transfected into EV71 infected RD cells and it was found that the overexpression of USP4 decreased the mRNA and protein expression of EV71 and VP1, inhibiting the replication of EV71, while also reducing RD cell apoptosis.
30194441
USP4 affects UL83
| 1
USP4 decreases the amount of UL83. 1 / 1
| 1
reach
USP4 silencing in LPS induced activation of microglia promoted the expression of p-p65 and TRAF6 and the secretion of TNF-alpha and IL-1beta.
28755289
USP4 affects TRIM25
| 1
USP4 activates TRIM25. 1 / 1
| 1
reach
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.
31792373
USP4 affects TCF_LEF
| 1
USP4 increases the amount of TCF_LEF. 1 / 1
| 1
reach
As NLK positively regulates Wnt signalling it appears that either NLK regulates USP4 nuclear localization as part of negative feedback loop to downregulate TCF or that NLK enhances USP4 mediated stabi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
28923280
USP4 affects TAB1
| 1
USP4 inhibits TAB1. 1 / 1
| 1
reach
USP4 inhibits TAK1 and TAB1 co-overexpression-mediated NF-kappaB activation.
21331078
USP4 affects Survival
| 1
USP4 activates Survival. 1 / 1
| 1
eidos
In addition , USP4 reportedly mediates cell proliferation , survival and metastasis ( 32 , 33 ) .
33178601
USP4 affects SMURF2
| 1
USP4 decreases the amount of SMURF2. 1 / 1
| 1
reach
In addition, inhibition of Ubiquitin carboxyl-terminal hydrolase 4 (USP4) decreased TGF- beta1 induced expression of TbetaR-I and reversed the altered expression of Smad7, Smurf2, ZO-1 and Vimentin.
25885904
USP4 affects SMAD2
| 1
USP4 increases the amount of SMAD2. 1 / 1
| 1
reach
TGF-betaR inhibition reduced level of TGF-betaR1, p-smad2 and p-ERK1/2 which can partially be rescued by USP4 overexpression.
30881035
USP4 affects SART3
| 1
USP4 activates SART3. 1 / 1
| 1
reach
Linker between DUSP and UBL domains of USP4 mediates SART3 binding.
27060135
USP4 affects Rln1
| 1
USP4 activates Rln1. 1 / 1
| 1
reach
Treatment with RLX siRNAs, TGF-beta1 siRNAs, Smad2 siRNAs or BB94 (MMPs inhibitor) to USP4 overexpressing breast cancer cells revealed that USP4- induced RLX via TGF-beta1 pathway promotes the cell migration and invasion.
27049265
USP4 affects RUNX2
| 1
USP4 activates RUNX2. 1 / 1
| 1
reach
19 A recent study has demonstrated that USP4 could promote osteoblast differentiation via Activation of Wnt and beta-catenin signalling by inducing Runx2.
33434305
USP4 affects RPS15
| 1
USP4 activates RPS15. 1 / 1
| 1
reach
USP4 remove the K48‐linked ubiquitination of RIG‐I and promotes RIG‐I signaling.
28744851
USP4 affects RPA
| 1
USP4 activates RPA. 1 / 1
| 1
reach
As shown in Figures 5 A-5D, WT USP4, but not the insert domain deletion mutant, restored CtIP and downstream RAD51 and RPA foci in USP4 depleted cells after IR.
26387952
USP4 affects RI
| 1
USP4 decreases the amount of RI. 1 / 1
| 1
reach
Importantly, depressed expression of USP4 inhibited TβRI expression and partially reversed EMT stimulated by TGF-β1.In the meantime, blunted phosphorylation of Akt promoted the E-cadherin expression, and inhibited α-SMA and Vimentin expression in response to TGF-β1.
27534765
USP4 affects REST
| 1
USP4 inhibits REST. 1 / 1
| 1
reach
However, neither USP4 nor USP11 depletion reduced REST in the initial screen; in fact, both these DUBs fell at the opposite end of the ranked data set (XREF_FIG).
23708518
USP4 affects RECQL4
| 1
USP4 inhibits RECQL4. 1 / 1
| 1
reach
There was a main effect of Distracter Type on RT latency, such that PLE (M = 448.53, SE = 11.95) and UNP (M = 446.91, SE = 11.95) produced slower RTs to subsequent targets than CIG (M = 441.39, SE = 11.95) or NEU (M = 437.92, SE = 11.95), F (3,150) = 5.75, p =.0009.
27097731
USP4 affects RAD51
| 1
USP4 activates RAD51. 1 / 1
| 1
reach
As shown in Figures 5 A-5D, WT USP4, but not the insert domain deletion mutant, restored CtIP and downstream RAD51 and RPA foci in USP4 depleted cells after IR.
26387952
USP4 affects PTP4A3
| 1
USP4 activates PTP4A3. 1 / 1
| 1
reach
It was recently found that deubiquitinating enzyme USP4 promotes PRL-3 stabilization in colon cancer cells.
28482095
USP4 affects PLAUR
| 1
USP4 decreases the amount of PLAUR. 1 / 1
| 1
reach
As shown in XREF_FIG, the upregulation of USP4 significantly inhibited the expression of u-PAR, MAP4K1 and c-Jun, and the knockdown of USP4 significantly upregulated the expression of u-PAR, MAP4K1 and c-Jun (XREF_FIG).
27430936
USP4 affects PDPK1
| 1
USP4 inhibits PDPK1. 1 / 1
| 1
reach
Although the great majority of DUBs was expressed at high levels (XREF_SUPPLEMENTARY), only the Ubiquitin Specific Protease 4 (USP4) reproducibly inhibited Ub-PDK1 (XREF_FIG).
22347420
USP4 affects PCNA
| 1
USP4 increases the amount of PCNA. 1 / 1
| 1
reach
Inhibition of USP4 downregulated the expression of PCNA, Bcl-2 and p-ERK1/2, but upregulated the expression of Bax both in vitro and in vivo.
30881035
USP4 affects P12
| 1
USP4 bound to SMAD4 activates P12. 1 / 1
| 1
reach
The binding of USP4 to SMAD4 prevents its monoubiquitination in the cytoplasm and subsequently enhances SMAD4 mediated activin and bone morphogenetic protein (BMP) pathways.
33681193
USP4 affects NSMAF
| 1
USP4 activates NSMAF. 1 / 1
| 1
reach
Knockdown of USP4 promoted IL-1beta, LPS, and TGF-beta-induced NF-kappaB activation (Fan et al., 2011).
27155333
USP4 affects NFKBIA
| 1
USP4 activates NFKBIA. 1 / 1
| 1
reach
This was further supported by knockout of USP4 aiding IkappaBalpha degradation [XREF_BIBR].
31208841
USP4 affects NELFE
| 1
USP4 activates NELFE. 1 / 1
| 1
reach
It was found that over-expression of USP4 enhanced the ability of RD cells to fight against invading EV71, and also reduced cell apoptosis.
30194441
USP4 affects MYOD1
| 1
USP4 inhibits MYOD1. 1 / 1
| 1
reach
Ubiquitin specific protease 4 (USP4) suppresses myoblast differentiation by down regulating MyoD activity in a catalytic independent manner.
28336234
USP4 affects MMP9
| 1
USP4 increases the amount of MMP9. 1 / 1
| 1
reach
Also, USP4 mediates the activation of TGF-beta1 and upregulates the expression of matrix metalloproteinase-9 (MMP-9), which mediates the migration and invasion of breast cancer cells [XREF_BIBR].
32308208
USP4 affects MDM2
| 1
USP4 inhibits MDM2. 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
USP4 affects MAPK
| 1
USP4 activates MAPK. 1 / 1
| 1
reach
We demonstrated that USP4 drives HCC progression by stabilizing CypA through direct interaction and deubiquitination and thus constitutively activates the MAPK and CrkII signaling pathways.
29396555
USP4 affects MAP4K1
| 1
USP4 decreases the amount of MAP4K1. 1 / 1
| 1
reach
As shown in XREF_FIG, the upregulation of USP4 significantly inhibited the expression of u-PAR, MAP4K1 and c-Jun, and the knockdown of USP4 significantly upregulated the expression of u-PAR, MAP4K1 and c-Jun (XREF_FIG).
27430936
USP4 affects JUN
| 1
USP4 decreases the amount of JUN. 1 / 1
| 1
reach
As shown in XREF_FIG, the upregulation of USP4 significantly inhibited the expression of u-PAR, MAP4K1 and c-Jun, and the knockdown of USP4 significantly upregulated the expression of u-PAR, MAP4K1 and c-Jun (XREF_FIG).
27430936
USP4 affects Interferon
| 1
USP4 activates Interferon. 1 / 1
| 1
reach
Congruently, the overexpression of USP4 or USP17 significantly promotes virus-induced IFN production and thereby restricts virus replication, whereas the knockdown of USP4 or USP17 has the opposite effect (77, 87).
34707613
USP4 affects IL4
| 1
USP4 inhibits IL4. 1 / 1
| 1
reach
Compared to the lung cells isolated from WT mice, Usp4 -/- lung cells decreased secretion of IL-4, IL-13 and IL-17A upon stimulation in vitro.
34144056
USP4 affects IL2RA
| 1
USP4 increases the amount of IL2RA. 1 / 1
| 1
reach
USP4 deficiency enhances CD25 expression and CD4 T-cell proliferation without impeding T-cell development.
22101742
USP4 affects IL17A
| 1
USP4 inhibits IL17A. 1 / 1
| 1
reach
Compared to the lung cells isolated from WT mice, Usp4 -/- lung cells decreased secretion of IL-4, IL-13 and IL-17A upon stimulation in vitro.
34144056
USP4 affects IL13
| 1
USP4 inhibits IL13. 1 / 1
| 1
reach
Compared to the lung cells isolated from WT mice, Usp4 -/- lung cells decreased secretion of IL-4, IL-13 and IL-17A upon stimulation in vitro.
34144056
USP4 affects HAS2
| 1
USP4 increases the amount of HAS2. 1 / 1
| 1
reach
These results suggest that USP4 and Lys190 of HAS2 are important for HAS2 protein expression, but not for stability, and that USP17 and USP4 differentially modulate HAS2 protein levels.
28604766
USP4 affects Fibrosis
| 1
USP4 inhibits Fibrosis. 1 / 1
| 1
eidos
In conclusion , USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver .
33295107
USP4 affects EIF6
| 1
USP4 increases the amount of EIF6. 1 / 1
| 1
reach
Although USP4 slightly enhanced the expression of eIF3a, it did not increase the nuclear localization of eIF3a, which partially supports that the nuclear localization effect of USP4 is specific to bet[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
26189775
USP4 affects DNA Damage
| 1
USP4 activates DNA Damage. 1 / 1
| 1
reach
In contrast, silencing USP4 by shRNA remarkably increased the p53 activity in response to DNA damage or not (XREF_FIG).
26411366
USP4 affects Collagen
| 1
USP4 decreases the amount of Collagen. 1 / 1
| 1
reach
In the present study, the down-regulation of USP4 induced reduced expression of collagen I, collagen III, fibronectin, and alpha-SMA mRNAs in hypertrophic scar fibroblasts.
32308208
USP4 affects CXCL8
| 1
USP4 activates CXCL8. 1 / 1
| 1
reach
Again, there was little effect of NP size on IL-6 release, whereas 100nm UNP and CNP induced more IL-8 release than did the 50nm NPs.
26133975
USP4 affects CAT
| 1
USP4 inhibits CAT. 1 / 1
| 1
reach
The deletion of the insert significantly reduces the activity of USP4 FL (approximately sevenfold reduction in k cat, XREF_FIG; XREF_TABLE).
25404403
USP4 affects C6orf89
| 1
USP4 activates C6orf89. 1 / 1
| 1
reach
As expected, the FLAG antibody detects bands coinciding with the higher molecular weight forms of myc-BRAP induced by the expression of catalytically inactive USP4 and 15, which are absent in the case of mutant myc-BRAP-WA (XREF_FIG A, compare lanes 2 and 4 with 9 and 11).
23105109
USP4 affects BCL2
| 1
USP4 increases the amount of BCL2. 1 / 1
| 1
reach
Inhibition of USP4 downregulated the expression of PCNA, Bcl-2 and p-ERK1/2, but upregulated the expression of Bax both in vitro and in vivo.
30881035
USP4 increases the amount of Auxin response factor. 1 / 1
| 1
reach
Two AUX/IAA (auxin response factors repressors) genes showed non significant change in expression pattern at UNP vs 12 HAP, which promotes the transcription of ARF (AUXIN RESPONSIVE FACTORS) at 12 HAP.
33823793
USP4 affects ATPase
| 1
USP4 inhibits ATPase. 1 / 1
| 1
reach
Effect of ATP on menadione inhibition of UNP stimulated ATPase.
14236650
USP4 affects AQP2
| 1
USP4 activates AQP2. 1 / 1
| 1
reach
In mpkCCD14 cells, shRNA mediated knockdown of USP4 decreased AQP2 protein abundance, whereas no changes in AQP2 mRNA levels or VP induced cAMP production were detected.
30901874
reach
Flow-cytometry-based quantification established that USP4 depletion (XREF_FIG E), but not SART3 depletion (XREF_SUPPLEMENTARY I), reduced native BrdU staining intensities in replicating cells without USP4 or SART3 depletion affecting protein levels of key resection factors (XREF_SUPPLEMENTARY J).
26455393
USP39 affects USP4
| 1
USP39 deubiquitinates USP4. 1 / 1
| 1
reach
USP39 binds with USP4 via its UBL domain and correspondingly enhances the stability of USP4 in T cells [XREF_BIBR, XREF_BIBR], implying that USP39 might be deubiquitylating USP4.
28659380
UBB affects USP4
| 1
UBB inhibits USP4. 1 / 1
| 1
reach
Moreover, mutating such cysteine residues to alanine prevented USP4 retrieval by HA-ubiquitin, restored the ability of catalytically dead USP4 to interact with CtIP and MRN, and also restored the ability of catalytically inactive USP4 to promote DSB repair, even in the absence ofendogenous USP4.
26455393
TGFB1 affects USP4
| 1
TGFB1 activates USP4. 1 / 1
| 1
reach
The Effects of the Transforming Growth Factor-beta1 (TGF-beta1) Signaling Pathway on Cell Proliferation and Cell Migration are Mediated by Ubiquitin Specific Protease 4 (USP4) in Hypertrophic Scar Tissue and Primary Fibroblast Cultures.
32308208
TGFB affects USP4
| 1
TGFB increases the amount of USP4. 1 / 1
| 1
reach
We also found that TGF-β1 upregulated USP4 expression in NRK-52E cells during their EMT.
27534765
SOX2 affects USP4
| 1
SOX2 activates USP4. 1 / 1
| 1
eidos
SOX2 Modulates the USP4 / SMAD4 / CK2 Axis via miR-30e Upregulation to Induce the Tumor Growth of EC in Nude Mice After overexpression of SOX2 , the expression of miR-30e and CK2 was increased and that of USP4 and SMAD4 was decreased .
33376627
SMAD4 affects USP4
| 1
Ubiquitinated SMAD4 increases the amount of USP4. 1 / 1
| 1
reach
Studies have shown that SOX2 increases the expression of the microRNA (miRNA) miR-30e, which decreases the expression of ubiquitin carboxyl-terminal hydrolase 4 (USP4), increasing ubiquitination and proteasomal degradation of mothers against decapentaplegic homolog 4 (SMAD4).
| PMC
RNA, Small Interfering inhibits USP4. 1 / 1
| 1
eidos
In contrast , cells treated with the chemotherapeutic TMZ were significantly more sensitive to USP4 depletion by siRNA and showed decreased cell viability .
33324551
Protease affects USP4
| 1
Protease activates USP4. 1 / 1
| 1
reach
The Effects of the Transforming Growth Factor-beta1 (TGF-beta1) Signaling Pathway on Cell Proliferation and Cell Migration are Mediated by Ubiquitin Specific Protease 4 (USP4) in Hypertrophic Scar Tissue and Primary Fibroblast Cultures.
32308208
Plant Extracts affects USP4
1 |
Plant Extracts increases the amount of USP4. 1 / 1
1 |
ctd
No evidence text available
23557933
PITX2 affects USP4
1 |
PITX2 decreases the amount of USP4. 1 / 1
1 |
biopax:msigdb
No evidence text available
PI3K affects USP4
| 1
PI3K increases the amount of USP4. 1 / 1
| 1
reach
Therefore, these results suggest that gastrodin stimulates the PI3K/AKT pathway and that activation of the PI3K/AKT pathway promotes USP4 expression by enhancing the phosphorylation of GATA1 in HepG2 cells.
| PMC
NES affects USP4
| 1
NES activates USP4. 1 / 1
| 1
reach
The function of the DUSP and UBL domains are unknown while the NES works in concert with a C-terminal nuclear localization (NLS), enabling the nuclear cytoplasmic shuttling of USP4 [23].
23022198
NBN affects USP4
| 1
NBN activates USP4. 1 / 1
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To further confirm that NBS1-USP4 interaction is indeed involved in NBS1 mediated USP4 recruitment, we stably transfected DR-GFP cells with NBS1 shRNA and reconstituted these cells with shRNA resistan[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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K63 affects USP4
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K63 activates USP4. 1 / 1
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Coronaviruses (CoVs) are a large family of RNA viruses that cause respiratory tract infections, ranging from the mild common cold to serious diseases such as severe acute respiratory syndrome (SARS), middle east www.advancedsciencenews.com www.advancedscience.com Inhibiting TLR/NF-B signaling [ 100] TRIF USP19 K27 Inhibiting TLR3/4-mediated signaling [98] TRAF6 A20 K63 Terminating TLR-induced activity [91] USP4 K63 Preventing NF-B and AP1 activation, inhibiting TLR/IL-1R signaling [ 102] USP 10 K63 Interacting with TANK and MCPIP1, terminating NF-B activation in response to TLR [ 104] MYSM1 K63 Terminating TLR-mediated antiviral responses [ 101] OTUD1 K48 Inhibiting IFN production [ 175] OTUB1/2 K63 Inhibiting antiviral responses [ 172] TRAF3 MYSM1 K63 Terminating TLR-mediated antiviral responses [ 101] UCHL1 K63 Inhibiting IFN production [ 103] OTUD1 K48 Inhibiting IFN production [ 175] OTUB1/2 K63 Inhibiting antiviral responses [ 172] RIP1 (also known as RIPK1) A20 K63 Inhibiting NF-B signaling [92] CYLD K63 Inhibiting NF-B signaling [95] A20 K48 Inducing A20 degradation with E3 ligase activity, inhibiting NF-B signaling [92] NEMO A20 N/A Binding to ubiquitinated NEMO, blocking IKK phosphorylation, inhibiting NF-B activation [93] CYLD M1 Inhibiting NF-B signaling [97] USP10 M1 Interacting with NEMO via MCPIP1, inhibiting the genotoxic NF-B signaling [40] TAK1 USP18 K63 Inhibiting TLR/NF-B signaling [ 116] RIG-I USP5 K48 Interacting with STUB1, mediating RIG-I degradation, enhancing VSV replication [ 174] CYLD K63 Inhibiting IFN production [ 162] USP3 K63 Inhibiting antiviral responses upon viral infection [ 164] USP21 K63 Inhibiting antiviral responses [ 165] USP14 K63 Inhibiting antiviral responses [ 167] USP27X K63 Inhibiting antiviral responses [ 168] USP15 K63 Inhibiting antiviral responses [ 169] MAVS YOD1 K63 Inhibiting IRF3 and p65 activation, IFN-production, inhibiting antiviral responses [ 170] OTUD1 K48 Inhibiting IFN production [ 175] OTUD3 K63 Inhibiting antiviral responses [ 171] STING USP49 K63 Inhibiting antiviral responses after HSV-1 infection [ 217] USP21 K63 Inhibiting type I interferon production induced by DNA virus [ 219] USP13 K27/33 Impairing the recruitment of TBK1 to STING, inhibiting antiviral responses [ 218] USP21 K27 Inhibiting type I interferon production induced by DNA virus [ 219] USP22 K27 Interacting with USP13 [ 174] TBK1 A20 K63 Inhibiting antiviral responses with TAX1BP1 [ 232] USP2b K63 inhibiting TBK1 kinase activity, terminating TBK1 activation, inhibiting IFN-signaling [ 233] USP7 K48 Interacting with and stabilizing TRIM27, inhibiting antiviral type I IFN signaling [ 235] USP38 K33 Interacting with TBK1 via NLRP4, allowing DTX4-and TRIP-mediated K48-linked polyubiquitination, promoting TBK1 degradation, inhibiting IFN-I signaling [ 236] IRF3 OTUD1 K63 Inhibiting IRF3 nuclear translocation and its transcriptional activity [ 244] K6 Disassociation of IRF3 from the promoter region of target genes, inhibiting type I IFN induction [ 245] Signaling activation TRAF3 USP25 K48 Preventing TRAF3 degradation following virus infection, facilitating antiviral responses [ 117, 180] OTUD7B K48 Inhibiting TRAF3 proteolysis, preventing aberrant non-canonical NF-B activation [ 118] RIG-I USP15 K63 Removing K48-linked polyubiquitin chains on TRIM25, promoting IFN-I expression [ 181] USP4 K48 Stabilizing RIG-I, prolonging IFN induction [ 177] USP17 K48 Stabilizing RIG-I, facilitating antiviral responses [ 176] (Continued) Adv.
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INSR affects USP4
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INSR inhibits USP4. 1 / 1
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Gastrodin Enhanced Insulin Receptor Expression and Decreased the Ubiquitin Level of the Insulin Receptor via USP4 in HepG2 Cells.
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HNRNPD affects USP4
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HNRNPD increases the amount of USP4. 1 / 1
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Moreover, HNRNPD deficiency significantly increased USP4 expression at mRNA and protein levels, accompanied by a increase of USP4-CDS luciferase activity.
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HIF1A affects USP4
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HIF1A decreases the amount of USP4. 1 / 1
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biopax:msigdb
No evidence text available
GPM6A affects USP4
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GPM6A decreases the amount of USP4. 1 / 1
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Subsequent studies demonstrated that m 6 A could decrease USP4 expression by inducing m 6 A dependent decay of the USP4 transcript.
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GLI3 affects USP4
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GLI3 inhibits USP4. 1 / 1
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PHS damage elevated endoprotease activity and consequently increased the degradation of polymeric UNP and free asparagine concentration in wheat samples.
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FOLH1 affects USP4
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FOLH1 inhibits USP4. 1 / 1
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For the second step, a copper assisted click reaction was undertaken between the azide functionalized version of the nanoparticles, either PSMA targeted TNP or untargeted UNP, and alkyne-function-alized 111 In-DOTA-PEG-alkyne from step 1.
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EGR3 affects USP4
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EGR3 decreases the amount of USP4. 1 / 1
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biopax:msigdb
No evidence text available
EGR2 affects USP4
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EGR2 decreases the amount of USP4. 1 / 1
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biopax:msigdb
No evidence text available
Dietary Fats affects USP4
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Dietary Fats increases the amount of USP4. 1 / 1
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ctd
No evidence text available
19467301
DUSP affects USP4
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DUSP activates USP4. 1 / 1
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The structure of USP4 and USP15 DUSP-Ubl has shown some degree of flexibility between the two domains XREF_BIBR XREF_BIBR, suggesting that the movement of the DUSP relative to the Ubl domain may be required to activate USP4.
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DNPEP affects USP4
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DNPEP activates USP4. 1 / 1
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Furthermore, we identify USP4 as a downstream target of the PAK5-DNPEP pathway; DNPEP mediates USP4 downregulation.
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DDX58 affects USP4
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DDX58 activates USP4. 1 / 1
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Similarly, in vesicular stomatitis virus (VSV) infection, removing K48 linked polyubiquitin chains from RIG-I allows USP4 to enhance RIG-I-triggered IFN-beta signaling, thereby inducing an antiviral immune response.
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CPSF3 affects USP4
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CPSF3 inhibits USP4. 1 / 1
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Interestingly, depletion of CPSF73 substantially reduced Pol II unph, S2P, and S5P pausing over the TES (XREF_FIG A).
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Brodifacoum affects USP4
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Brodifacoum increases the amount of USP4. 1 / 1
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ctd
No evidence text available
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Antirheumatic Agents decreases the amount of USP4. 1 / 1
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ctd
No evidence text available
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AVP affects USP4
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AVP activates USP4. 1 / 1
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USP4 co-localized with AQP2 in the mouse kidney, and in mpkCCD14 cells USP4 and AQP2 abundance are increased by VP.
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ARHGDIA affects USP4
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ARHGDIA inhibits USP4. 1 / 1
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As predicted, we found that METTL3 overexpression induced ARHGDIA expression, but downregulated ELAVL1 and USP4 (XREF_SUPPLEMENTARY).
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AHR affects USP4
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AHR decreases the amount of USP4. 1 / 1
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biopax:msigdb
No evidence text available
4-hydroxyphenyl retinamide increases the amount of USP4. 1 / 1
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ctd
No evidence text available
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3,4-methylenedioxymethamphetamine increases the amount of USP4. 1 / 1
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ctd
No evidence text available
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2,3,7,8-tetrachlorodibenzodioxine increases the amount of USP4. 1 / 1
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ctd
No evidence text available
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17alpha-ethynylestradiol increases the amount of USP4. 1 / 1
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ctd
No evidence text available
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4,4'-diaminodiphenylmethane decreases the amount of USP4. 1 / 1
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ctd
No evidence text available
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3,4,3',4'-tetrachlorobiphenyl increases the amount of USP4. 1 / 1
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ctd
No evidence text available
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2,2',4,4'-tetrabromodiphenyl ether increases the amount of USP4. 1 / 1
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ctd
No evidence text available
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