USP19 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 19
HGNC Gene Symbol
USP19
Identifiers
hgnc:12617 NCBIGene:10869 uniprot:O94966
Orthologs
mgi:1918722 rgd:1303276
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP19
Number of Papers
64 retrieved on 2022-05-22

DepMap Analysis

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

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

DepMap Correlations

Symbol Name DepMap Correlation Evidence CCLE Correlation CCLE Z-score CCLE p-value (adj) CCLE Significant CMAP Score CMAP Type
APEH acylaminoacyl-peptide hydrolase 0.277 Reactome (1) 0.47 2.49 4.60e-20
GLT8D1 glycosyltransferase 8 domain containing 1 0.257 0.11 0.54 6.40e-02
UBR4 ubiquitin protein ligase E3 component n-recognin 4 0.247 0.38 2.03 3.34e-13
KLHDC8B kelch domain containing 8B 0.242
IQCF1 IQ motif containing F1 0.24
GNAT1 G protein subunit alpha transducin 1 0.239
NAA80 N-alpha-acetyltransferase 80, NatH catalytic subunit 0.236

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP19using 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 USP19 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
RPS21 ribosomal protein S21 1.43e+00 5.82e-23 1.14e-19
VIM vimentin 6.48e-01 7.18e-11 7.04e-08
ANXA2 annexin A2 2.87e-01 3.12e-05 2.04e-02
APIP APAF1 interacting protein 5.38e-01 6.32e-05 2.93e-02
MTCH2 mitochondrial carrier 2 3.41e-01 7.47e-05 2.93e-02
TXNL1 thioredoxin like 1 4.59e-01 1.29e-04 3.60e-02
CFAP251 cilia and flagella associated protein 251 -7.23e-01 1.27e-04 3.60e-02
IFIT2 interferon induced protein with tetratricopeptide repeats 2 6.00e-01 1.50e-04 3.67e-02
FTL ferritin light chain 2.87e-01 2.20e-04 4.37e-02
PRRG3 proline rich and Gla domain 3 3.60e-01 2.25e-04 4.37e-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 USP19 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 lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
USP19 deubiquitinates SYVN1. 4 / 4
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We demonstrate that USP19 rescues HRD1 from proteasomal degradation by deubiquitination of K48-linked ubiquitin chains.

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USP19 negatively regulates the ubiquitination of HRD1 and prevents it from undergoing proteasomal degradation.

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These results suggest that USP19 deubiquitinates HRD1.

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USP19 Deubiquitinates HRD1.
USP19 deubiquitinates BECN1. 3 / 3
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Conversely, reversal of Beclin1 ubiquitylation by the DUB protein USP19 stabilized the protein under starvation conditions and promoted autophagy.

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USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin-1

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USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin-1.
USP19 deubiquitinates RNF123. 3 / 3
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USP19 deubiquitinates and stabilizes KPC1, an E3 ligase for p27.
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USP19 deubiquitinates Kip1 ubiquitination-promoting complex protein 1 (KPC1) regulating p27Kip1

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USP19 deubiquitinates and stabilizes KPC1, an E3 ligase for p27.
USP19 deubiquitinates CORO2A. 2 / 2
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And USP19 deubiquitinated CORO2A, suggesting that USP19 might have function to stabilize NCoR co and repressor complex in cells.

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Ubiquitin specific protease 19 involved in transcriptional repression of retinoic acid receptor by stabilizing CORO2A
USP19 deubiquitinates MARCHF6. 2 / 2
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In this study, we show that USP19 deubiquitinates and stabilizes MARCH6.

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USP19 was found to protect MARCH6 by deubiquitination from the p97-dependent proteasomal degradation.
USP19 deubiquitinates LRP6. 2 / 2
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Upon release from this putative ubiquitin binding chaperone, LRP6 is deubiquitinated by USP19.

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We show that folding of the Wnt signaling coreceptor LRP6 is promoted by ubiquitination of a specific lysine, retaining it in the ER while avoiding degradation. Subsequent ER exit requires removal of ubiquitin from this lysine by the deubiquitinating enzyme USP19.
Modified USP19 leads to the deubiquitination of MARCHF6. 2 / 2
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We also show that USP19 overexpression reduced ubiquitination of MARCH6, while its knockdown had the opposite effect.

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USP19 overexpression reduces the K48 linked ubiquitination of MARCH6.
USP19 deubiquitinates HDAC1. 1 / 1
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USP19 deubiquitinates HDAC1/2 to regulate DNA damage repair and control chromosomal stability
USP19 deubiquitinates NR3C1. 1 / 1
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Thus, USP19 modulates GR levels and in so doing may modulate both insulin and glucocorticoid signaling, two critical pathways that control protein turnover in muscle and overall glucose homeostasis.
USP19 deubiquitinates BIRC2. 1 / 1
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No evidence text available
USP19 deubiquitinates FUNDC1. 1 / 1
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In response to hypoxia, USP19 binds to and deubiquitinates FUNDC1 at ER-mitochondria contact sites, which facilitates Drp1 oligomerization and Drp1 GTP binding and hydrolysis activities, thereby promoting mitochondrial division.
USP19 deubiquitinates E3_Ub_ligase. 1 / 1
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USP19 deubiquitinates and stabilizes KPC1, an E3 ligase for p27.
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USP19 deubiquitinates HDAC2. 1 / 1
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USP19 deubiquitinates HDAC1/2 to regulate DNA damage repair and control chromosomal stability
USP19 deubiquitinates TRAF3. 1 / 1
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USP19 suppresses cellular type I interferon signaling by targeting TRAF3 for deubiquitination
USP19 deubiquitinates MAP3K7. 1 / 1
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These observations suggest that USP18 and USP19 deubiquitinate TAK1 in a cell type specific dependent manner.
USP19 deubiquitinates BIRC3. 1 / 1
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No evidence text available
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In contrast, our studies have clearly demonstrated that USP19 catalytic activity is essential for its effects on differentiation and argue that USP19 is deubiquitinating an ER localized protein that represses the ER stress response.
USP19 deubiquitinates CDKN1B. 1 / 1
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USP19 deubiquitinates and stabilizes KPC1, an E3 ligase for p27.
| PMC

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
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USP19-ER inhibited both muscle cell differentiation and the unfolded protein response gene CHOP that occurs during differentiation.

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USP19 can inhibit myogenic differentiation through suppression of an unfolded protein response that is required for muscle cell fusion xref .

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These results suggested that USP19 inhibits muscle cell differentiation by suppressing the differentiation dependent induction of the UPR during myogenesis.

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USP19 can inhibit myogenic differentiation through suppression of an unfolded protein response that is required for muscle cell fusion 74.

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These results suggested that USP19 inhibits muscle cell differentiation by suppressing the differentiation-dependent induction of the UPR during myogenesis.

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Because USP19 inhibits differentiation, it was somewhat surprising to observe its induction during differentiation.

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In the case of USP19, we have also provided evidence that this modulation of UPR signaling may also occur in vivo during myogenic regeneration in response to muscle injury and that loss of USP19 can lead to a more rapid differentiation and larger myofibers (XREF_FIG).

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Consistent with this, our recent studies also demonstrate that overexpression of USP19 can impair muscle cell differentiation in vitro (unpublished data).

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USP19 deubiquitinating enzyme inhibits muscle cell differentiation by suppressing unfolded protein response signaling.

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Because USP19 inhibits differentiation, it was somewhat surprising to observe its induction during differentiation.
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These results suggested that USP19 inhibits muscle cell differentiation by suppressing the differentiation dependent induction of the UPR during myogenesis.

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Our previous observations that silencing USP19 induced expression of myofibrillar proteins as well as myogenin in muscle cells suggested that USP19 might modulate muscle cell differentiation.

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We therefore tested whether USP19 modulates this differentiation dependent CHOP induction and, if so, whether it requires ER localization.

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These results indicated that USP19 enhanced cell proliferation and exhibited anti-apoptotic properties.

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USP19 deubiquitinating enzyme supports cell proliferation by stabilizing KPC1, a ubiquitin ligase for p27Kip1.

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We previously reported that the USP19 deubiquitinating enzyme positively regulates proliferation in fibroblasts by stabilizing KPC1, a ubiquitin ligase for p27 Kip1.

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Reports indicate that the disruption of USP19 inhibits a series of PCa cell proliferation by arresting cells in the G1 to S phase transition through stabilization of the cyclin-dependent kinase inhibitor p27 .
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The results showed that knockdown of USP19 suppressed cell proliferation in SGC7901 cells while overexpressing USP19 accelerated cell growth in GES1 cells, as determined by MTT assay (P < 0.01, XREF_FIG and XREF_FIG).

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Opposite to our findings, Hu and collaborators recently demonstrated that USP19 negatively regulates proliferation and migration in clear cell renal carcinoma 69.

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USP19 overexpression inhibited ccRCC proliferation and migration, whereas USP19 knockdown promoted ccRCC proliferation and migration invitro.

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USP19 deubiquitinates and thereby stabilizes the KPC1 ligase for p27 Kip1, and so indirectly promotes degradation of p27 Kip1 and subsequent cell proliferation.

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Depletion of USP19 inhibited proliferation in prostate cancer DU145, PC-3 and 22RV1 cells, which was similar to the pattern established in fibroblasts in that it was due to decreased progression from G1 to S phase and associated with a stabilization of the cyclin-dependent kinase inhibitor p27 Kip1 .

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Depletion of USP19 inhibited proliferation in prostate cancer DU145, PC-3 and 22RV1 cells, which was similar to the pattern established in fibroblasts in that it was due to decreased progression from G1 to S phase and associated with a stabilization of the cyclin dependent kinase inhibitor p27 Kip1.

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In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings.

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USP19 overexpression enhances migration and invasion.

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In our study, the cell invasion and migration induced by USP19 was correlated with MMP2 and MMP9 expression and enzyme activity.

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In accordance with our previous results, the USP19 dependent increase in invasion is also determined by its catalytic activity and presence of the transmembrane domain.

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Collectively, our results indicate that USP19 knockdown inhibits tumor cell invasion in vitro.

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USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life .

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USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer.

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Transwell assay showed that knockdown of USP19 decreased invasiveness of SGC7901 cells, whereas overexpression of USP19 enhanced GES1 cell invasion (P < 0.01; XREF_FIG and XREF_FIG, respectively).

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USP19 knockdown impairs invasion.
USP19 affects Interferon
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USP19 inhibits Interferon.
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By removing K11 linked chains at K437 from Beclin-1, an essential factor of autophagic initiation, USP19 induces autophagy and inhibits the production of type I IFN [XREF_BIBR].

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USP19 suppresses cellular type I interferon signaling by targeting TRAF3 for deubiquitination.

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Furthermore, USP19 negatively regulates type I interferon (IFN) signaling and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation [27,28].
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Previous studies have indicated that EV71 infection induces the up-regulation of USP19, which negatively regulates the antiviral type I interferon signalling by removing K-63 polyubiquitin chains from TRAF3 35.

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Furthermore, USP19 deficiency in macrophages caused an elevation of TBK1 and the activation of the type-I interferon signaling pathway after vesicular stomatitis virus (VSV) infection.

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The reduced expression of USP19 following MI and CHF could result in reduced autophagic response and could promote IFN signaling and NF-κB activation induced by tumor necrosis factor or interleukin 1β.
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USP19 activates Interferon.
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However, USP13, USP19, and USP22 inhibit virus-induced IFN production by removing K27-linked polyubiquitin chains from STING (40, 81) or TRIF (90).
USP19 affects CORO2A
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USP19 activates CORO2A.
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USP19 activates CORO2A. 3 / 5
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These results indicate that USP19 may prevent proteasomal degradation of CORO2A.

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The result showed that CORO2A was gradually increased by USP19 expression.

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Overexpression of USP19 inhibited RARE transcription and knock-down of USP19 using siRNA showed dramatically increased transcription of RARE, suggesting that USP19 increases the stability of CORO2A by DUB activity, and that binding of these two protein may be associated with the function of NCoR.
USP19 decreases the amount of CORO2A.
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USP19 decreases the amount of CORO2A. 1 / 1
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Since USP19 reduced the ubiquitination level of CORO2A, we next tested the expression level of CORO2A upon USP19 dose dependent expression.
USP19-C506S decreases the amount of CORO2A. 1 / 1
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However, the catalytic mutant USP19 (C506S) did not significantly decrease the ubiquitination level of CORO2A.
USP19 affects Mhc
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USP19 increases the amount of Mhc.
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USP19 increases the amount of Mhc. 4 / 4
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USP19 depletion also increased MHC and tropomyosin mRNA levels, suggesting that this effect is due to increased transcription.

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Depletion of all isoforms of USP19 increased myogenin (XREF_FIG) and tropomyosin and MHC protein levels (XREF_FIG), as previously reported, and enhanced myotube formation and fusion (XREF_FIG).

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USP19 depletion also increased MHC and tropomyosin mRNA levels, suggesting that this effect is due to increased transcription.

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Mutant forms of USP19 lacking deubiquitinating activity increased MHC and tropomyosin levels.
USP19 activates Mhc.
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USP19 activates Mhc. 2 / 2
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Depletion of USP19 reversed the dexamethasone suppression of MHC.

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USP19 siRNA reversed the suppression of MHC by these agents.
USP19 affects CDKN1B
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USP19 activates CDKN1B.
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USP19 activates CDKN1B. 3 / 4
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Indeed, in cells transfected with USP19 siRNA p27 Kip1 levels remained relatively stable over time whereas the half-life of the protein was significantly lower in controls (XREF_FIG), implying that USP19 modulates the stability of p27 Kip1.

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Although p27 Kip1 mRNA levels remain unchanged upon USP19 depletion (XREF_FIG), it remains possible that p27 Kip1 synthesis is regulated also at the level of translation and that USP19 modulates such translational efficiency of p27 Kip1 mRNA.

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This increased p27 Kip1 induced by USP19 depletion did not appear to be due to increased gene transcription, as Northern blot analysis revealed that p27 Kip1 mRNA levels did not change (XREF_FIG).
USP19 inhibits CDKN1B.
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USP19 inhibits CDKN1B. 2 / 2
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In their model, USP19 stabilizes KPC1 and thus indirectly promotes degradation of p27 KIP1 in the cytoplasm.

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USP19 deubiquitinates and thereby stabilizes the KPC1 ligase for p27 Kip1, and so indirectly promotes degradation of p27 Kip1 and subsequent cell proliferation.
USP19 affects SYVN1
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USP19 activates SYVN1.
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USP19 activates SYVN1. 2 / 4
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We demonstrate that USP19 rescues HRD1 from proteasomal degradation by deubiquitination of K48 linked ubiquitin chains.

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In this study, we found that overexpression of USP19 also increases the stability and steady-state expression levels of HRD1 in a manner dependent on its DUB activity (XREF_FIG A, XREF_FIG A and Figure S7).
USP19 inhibits SYVN1.
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USP19 inhibits SYVN1. 1 / 1
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This raises the possibility that USP19 might negatively regulate HRD1 mediated protein dislocation, thereby leading to increased expression of HRD1 itself.
USP19 increases the amount of SYVN1.
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USP19 increases the amount of SYVN1. 1 / 1
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Therefore, these results suggest that USP19 positively regulates the HRD1 level by protecting it from ERAD through a DUB activity dependent mechanism.
USP19 affects MMP9
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USP19 increases the amount of MMP9.
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USP19 increases the amount of MMP9. 4 / 4
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Our study suggests that USP19 promoted tumor progression by inducing MMP2 and MMP9 expression and related enzyme activity.

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Our results first indicated that USP19 enhanced MMP2 and MMP9 protein expression as well as enzyme activity.

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We first found overexpressing USP19 increased MMP2 and MMP9 protein levels.

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Moreover, the ability of USP19 to enhance the migratory and invasive abilities of GC cells by increasing MMP2 and MMP9 expression was evaluated using gelatin zymography.
Modified USP19 increases the amount of MMP9. 1 / 1
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Overexpression of USP19 enhanced MMP2 and MMP9 protein expression and enzyme activity.
USP19 activates MMP9.
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USP19 activates MMP9. 1 / 1
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USP19 Enhances MMP2 and MMP9 Mediated Tumorigenesis in Gastric Cancer.
USP19 affects MYOG
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USP19 increases the amount of MYOG.
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USP19 increases the amount of MYOG. 3 / 3
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The ability of USP19 to modulate expression of myogenin suggests that it might also be involved in myogenesis.

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The USP19 deubiquitinating enzyme modulates the expression of myogenin and myofibrillar proteins in L6 muscle cells.

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Only the ER localized isoform of USP19 (USP19-ER) modulated myoblast fusion as well as the expression of myogenin and myofibrillar proteins, and these effects were also dependent on USP19 catalytic activity.
USP19 inhibits MYOG.
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USP19 inhibits MYOG. 1 / 1
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They found that a decrease of USP19 promoted muscle cell fusion and increased myotube diameter and expressions of myogenin and myosin heavy chain.
USP19 decreases the amount of MYOG.
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USP19 decreases the amount of MYOG. 1 / 1
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USP19 inhibits fusion of L6 myoblasts and expression of myogenin and major myofibrillar proteins.
USP19 activates MYOG.
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USP19 activates MYOG. 1 / 1
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Our previous observations that silencing USP19 induced expression of myofibrillar proteins as well as myogenin in muscle cells suggested that USP19 might modulate muscle cell differentiation.
E2 affects USP19
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E2 increases the amount of USP19. 5 / 5
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These results demonstrate that in soleus muscle in young female mice under physiological conditions, E2 upregulates USP19 expression through ERalpha and consequently leads to decreases in ubiquitin conjugates and muscle mass.

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Furthermore, in skeletal muscle satellite cells, E2 inhibited myogenesis and increased USP19 expression, and diarylpropionitrile repressed E2 increased USP19 expression.

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Propylpyrazole-triol increased USP19 expression, and ICI 182,780 inhibited E2 increased USP19 expression.

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E2 replacement increased USP19 expression in the gastrocnemius and soleus muscles of ovariectomized mice.

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E2 induced ubiquitin specific peptidase 19 (USP19) expression during myogenesis.
USP19 affects MMP2
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USP19 increases the amount of MMP2.
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USP19 increases the amount of MMP2. 4 / 4
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Our results first indicated that USP19 enhanced MMP2 and MMP9 protein expression as well as enzyme activity.

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Our study suggests that USP19 promoted tumor progression by inducing MMP2 and MMP9 expression and related enzyme activity.

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Moreover, the ability of USP19 to enhance the migratory and invasive abilities of GC cells by increasing MMP2 and MMP9 expression was evaluated using gelatin zymography.

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We first found overexpressing USP19 increased MMP2 and MMP9 protein levels.
USP19 activates MMP2.
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USP19 activates MMP2. 1 / 1
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USP19 Enhances MMP2 and MMP9 Mediated Tumorigenesis in Gastric Cancer.
USP19 affects MARCHF6
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USP19 increases the amount of MARCHF6.
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USP19 increases the amount of MARCHF6. 3 / 3
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In support of this hypothesis, we showed that ABCB11 G238V was stabilized by the USP19 knockdown that reduced MARCH6 expression.

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Since enzyme activity is generally proportional to the protein expression levels, we expected that knockdown of USP19 would reduce MARCH6 expression, which in turn would stabilize the ABCB11 G238V mut[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Furthermore, we addressed whether knockdown of the endogenous USP19 protein with small interfering RNA (siRNA) would reduce the levels of endogenous MARCH6.
USP19 activates MARCHF6.
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USP19 activates MARCHF6. 2 / 2
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Further investigation is needed to elucidate the physiological significance of USP19 mediated stabilization of MARCH6, and also to identify novel substrates and regulatory factors.

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These results suggest that USP19 is likely to positively regulate the MARCH6 mediated ERAD of ABCB11 G238V.
USP19 affects tropomyosin
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USP19 increases the amount of tropomyosin. 4 / 4
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USP19 depletion also increased MHC and tropomyosin mRNA levels, suggesting that this effect is due to increased transcription.

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USP19 depletion also increased MHC and tropomyosin mRNA levels, suggesting that this effect is due to increased transcription.

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Depletion of all isoforms of USP19 increased myogenin (XREF_FIG) and tropomyosin and MHC protein levels (XREF_FIG), as previously reported, and enhanced myotube formation and fusion (XREF_FIG).

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Mutant forms of USP19 lacking deubiquitinating activity increased MHC and tropomyosin levels.
USP19 affects CFTR
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USP19 activates CFTR. 4 / 4
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In preceding studies the ER localised USP19 was shown to rescue the ERAD substrates cystic fibrosis transmembrane conductance regulator (CFTR) DeltaF508 and T-cell receptor-alpha (TCRalpha) from proteasomal degradation 109.

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Interestingly, USP19 is a target gene of the unfolded protein response (UPR) and was found to rescue CFTR DeltaF508 from ERAD.

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USP19 was reported to rescue the CFTR Delta508 mutant, which is an ERAD substrate.

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USP19 rescues the ERAD substrates cystic fibrosis transmembrane conductance regulator (CFTR) DeltaF508 and T-cell receptor-alpha (TCRalpha) from proteasomal degradation.
USP19 affects TBK1
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USP19 inhibits TBK1.
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USP19 inhibits TBK1. 2 / 2
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Furthermore, USP19 deficiency in macrophages caused an elevation of TBK1 and the activation of the type-I interferon signaling pathway after vesicular stomatitis virus (VSV) infection.

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Here, we demonstrate that USP19 (ubiquitin specific peptidase 19) interacts with and promotes TBK1 lysosomal degradation via chaperone-mediated autophagy (CMA).
USP19 activates TBK1.
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USP19 activates TBK1. 2 / 2
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USP19 (ubiquitin specific peptidase 19) promotes TBK1 (TANK-binding kinase 1) degradation via chaperone-mediated autophagy.

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We observed that TBK1 had a canonical CMA motif, knocking down key proteins involved in CMA (HSPA8/HSC70 or LAMP2A) or inhibiting CMA-prevented USP19-mediated TBK1 degradation.
USP19 affects SNCA
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USP19 activates SNCA.
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USP19 activates SNCA. 3 / 3
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Recently, the DUB, USP19, was shown to promote misfolded alpha-synuclein secretion [XREF_BIBR].

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However, under this condition, wild type (WT) USP19 is able to promote the secretion of misfolded alpha-Synuclein (alpha-Syn) in a dose dependent manner, as demonstrated previously 3.

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Although USP19 stimulates alpha-synuclein secretion, exosome dependent tau secretion is not enhanced.113 4 Alternative Spreading Mechanisms.
USP19 increases the amount of SNCA.
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USP19 increases the amount of SNCA. 1 / 1
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USP19 promoted the secretion of a-syn, suggesting that MAPS is an unconventional secretion pathway utilized by a-syn, particularly under conditions of proteasomal impairment, which has been repeatedly linked to Parkinson’s disease.
USP19 affects DDIT3
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USP19 increases the amount of DDIT3.
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USP19 increases the amount of DDIT3. 3 / 3
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The higher levels of CHOP mRNA seen during regeneration in the USP19 KO muscle suggest that USP19 modulates transcription of CHOP, but modulation of CHOP mRNA stability can not be excluded.

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First, USP19 (XREF_FIG) modulated the expression of CHOP, which had previously been shown to be the key marker of the ER stress response that occurs in only a small fraction of the differentiating myoblasts but is critical for differentiation.

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The mechanisms by which CHOP expression is modulated by USP19 will require further study.
USP19 activates DDIT3.
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USP19 activates DDIT3. 1 / 1
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We therefore tested whether USP19 modulates this differentiation dependent CHOP induction and, if so, whether it requires ER localization.
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Dexamethasone treatment lowered MHC and increased USP19.

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It is also possible that the deubiquitinating enzyme USP19, which is induced in atrophying skeletal muscle and stimulated by dexamethasone played a role in mediating the negative balance between muscle protein synthesis and proteolysis.

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Dexamethasone or TNF-alpha treatment lowered MHC and increased USP19.
Daidzein affects USP19
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Daidzein decreases the amount of USP19. 3 / 3
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Dietary daidzein down-regulated the expression of USP19 at the mRNA and protein levels and increased soleus muscle mass in female mice, but not in males.

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These results demonstrate that dietary daidzein decreases USP19 mRNA expression through ERbeta and increases soleus muscle mass in young female mice, but not in male mice, under physiological conditions.

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Daidzein stimulated the transcriptional activity of ERbeta in murine C2C12 cells and down-regulated USP19 expression.
USP19 affects SLC6A4
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USP19 activates SLC6A4. 3 / 3
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The major finding of this work is that cytoplasmic USP19 can promote aggregation of the polyQ expanded Atx3 and Htt proteins by up-regulating their protein levels.

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Based on these lines of evidence, we propose a model for triage decision of the Htt protein modulated by USP19 through HSP90.

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Our previous study has demonstrated that cytoplasmic ubiquitin specific protease 19 (USP19), through interacting with HSP90, up-regulates the protein levels of the N-terminal 552-residue fragments of Htt (Htt-N552) with normal and expanded polyQ, and consequently increases the aggregates formed by polyQ expanded Htt-N552 31.
USP19 affects LRP6
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USP19 activates LRP6. 2 / 3
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Finally, these observations demonstrate that USP19 promotes the biogenesis of LRP6, with only 18% of newly synthesized LRP6 molecules surviving beyond 6 hr in the absence of USP19 and 60% surviving upon USP19 overexpression.

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USP19 promotes LRP6 biogenesis and controls Wnt signaling.
USP19 affects ATXN3
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USP19 activates ATXN3. 3 / 3
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The major finding of this work is that cytoplasmic USP19 can promote aggregation of the polyQ expanded Atx3 and Htt proteins by up-regulating their protein levels.

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We next examined the effect of usp19 silencing on the protein levels of Atx3 100Q and Htt-N552 100Q, and observed that knockdown of USP19 significantly reduced the protein levels of Atx3 100Q (XREF_FIG) and Htt-N552 100Q (XREF_FIG) both in HEK 293T cells and in human retinal pigment epithelial (RPE1) cells (XREF_SUPPLEMENTARY).

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Cytoplasmic Ubiquitin Specific Protease 19 (USP19) Modulates Aggregation of Polyglutamine Expanded Ataxin-3 and Huntingtin through the HSP90 Chaperone.
USP19 affects autophagy
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USP19 activates autophagy.
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USP19 positively regulates autophagy by stabilizing Beclin-1, an essential autophagy protein, via deubiquitination [27].
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By removing K11 linked chains at K437 from Beclin-1, an essential factor of autophagic initiation, USP19 induces autophagy and inhibits the production of type I IFN [XREF_BIBR].
USP19 inhibits autophagy.
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USP19 inhibited NLRP3 inflammasome activation by increasing autophagy flux and decreasing the generation of mitochondrial reactive oxygen species.
USP19 affects NLRP3
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USP19 inhibits NLRP3.
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USP19 inhibits NLRP3. 2 / 2
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USP19 suppresses inflammation and promotes M2 like macrophage polarization by manipulating NLRP3 function via autophagy.

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USP19 inhibited NLRP3 inflammasome activation by increasing autophagy flux and decreasing the generation of mitochondrial reactive oxygen species.
USP19 activates NLRP3.
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USP19 activates NLRP3. 1 / 1
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In addition, USP19 inhibited the proteasomal degradation of inflammasome independent NLRP3 by cleaving its polyubiquitin chains.
ESR1 affects USP19
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ESR1 increases the amount of USP19.
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ESR1 increases the amount of USP19. 2 / 2
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These results demonstrate that (i) E2 induces USP19 expression through nuclear ERalpha, (ii) increased USP19 mediated deubiquitinating activity represses myogenesis, and (iii) ERbeta inhibits ERalpha activated USP19 expression.

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A mutant form of ERalpha that is constitutively localized in the nucleus increased USP19 expression and decreased MHC and tropomyosin expression in the presence of E2.
ESR1 decreases the amount of USP19.
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ESR1 decreases the amount of USP19. 1 / 1
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Knockdown of ERalpha in hindlimb muscles decreased Usp19 mRNA expression and increased the mass of soleus muscle only in females.
Estrogen affects USP19
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Estrogen increases the amount of USP19.
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Estrogen increases the amount of USP19. 1 / 1
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Collectively, the work by Ogawa and co-workers provides evidence that estrogen increases the expression of USP19 and contributes to muscle atrophy.
Estrogen decreases the amount of USP19.
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Estrogen decreases the amount of USP19. 1 / 1
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In support of this, estrogen acting via the ERalpha receptor can suppress differentiation and increase expression of USP19 in cultured muscle cells (Ogawa et al., 2011).
Estrogen activates USP19.
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Collectively , the work by Ogawa and co-workers provides evidence that estrogen increases the expression of USP19 and contributes to muscle atrophy .
Bisphenol A affects USP19
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Bisphenol A increases the amount of USP19. 2 / 2
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ctd
No evidence text available

ctd
No evidence text available
USP19 affects proteolysis
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USP19 suppresses protein synthesis and enhances protein degradation (ubiquitin proteasome system and autophagy) suggesting that it acts on an upstream signalling pathway (s).

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Conclusions : Loss of USP19 suppresses proteolysis upon glucocorticoid stimulation, but enhances protein synthesis upon fasting.
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eidos
USP19 suppresses inflammation and promotes M2-like macrophage polarization by manipulating NLRP3 function via autophagy .

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USP19 suppresses inflammation and promotes M2 like macrophage polarization by manipulating NLRP3 function via autophagy.

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Finally, these observations demonstrate that USP19 promotes the biogenesis of LRP6, with only 18% of newly synthesized LRP6 molecules surviving beyond 6 hr in the absence of USP19 and 60% surviving upon USP19 overexpression.

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USP19 promotes LRP6 biogenesis and controls Wnt signaling.
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Our results showed that USP19 positively regulated GC cell migration through the up-regulation of MMP2 and MMP9 expression and the decrease of cleaved caspase-3 activity in cell models (XREF_FIG and XREF_FIG).

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USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer.
USP19 affects cell growth
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The results showed that knockdown of USP19 suppressed cell proliferation in SGC7901 cells while overexpressing USP19 accelerated cell growth in GES1 cells, as determined by MTT assay (P < 0.01, XREF_FIG and XREF_FIG).

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Therefore, the USP19 modulation of prostate cancer cell growth occurs through a regulation of cell cycle progression from G0/G1 to S phase and does not affect the rate of apoptotic cell death.
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It has been also reported that USP19 inhibits TNFα -induced apoptosis via the stabilization of c-IAP s, which are ubiquitin ligases that regulate the stability of a variety of apoptotic and non-apoptotic proteins [ xref ].
USP19 affects RNF123
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USP19 activates RNF123. 1 / 2
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USP19 deubiquitinating enzyme supports cell proliferation by stabilizing KPC1, a ubiquitin ligase for p27Kip1.
USP19 affects RAR
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USP19 inhibits RAR. 2 / 2
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USP19 and CORO2A mediate the transcriptional repression of RAR.

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RAR target genes were decreased by the overexpression of CORO2A, and increased by the knockdown of USP19 (XREF_SUPPLEMENTARY).
USP19 affects HTT
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USP19 activates HTT. 2 / 2
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Cytoplasmic Ubiquitin Specific Protease 19 (USP19) Modulates Aggregation of Polyglutamine Expanded Ataxin-3 and Huntingtin through the HSP90 Chaperone.

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A mechanism of auto-inhibition of USP19 and activation by HSP90 is proposed, on which USP19 modulates the protein level of polyQ expanded huntingtin in cells.
USP19 affects BIRC3
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USP19 activates BIRC3. 2 / 2
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Furthermore, DUBs are known to regulate stability of only 4 of these proteins, including the ubiquitin ligases MARCH7 and BIRC3, which are targeted by USP7 or USP9 and USP19, respectively.

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For example, USP19 increased the stability of the cellular inhibitors of apoptosis 1 (c-IAP1) and c-IAP2 [XREF_BIBR].

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Overexpression of USP19 inhibited RARE transcription and knock-down of USP19 using siRNA showed dramatically increased transcription of RARE (Figure xref and Figure xref ), suggesting that USP19 increases the stability of CORO2A by DUB activity, and that binding of these two protein may be associated with the function of NCoR.

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100 Loss of USP19 increases transcription of myofibrillar proteins in L6 muscle cells and decreases muscle wasting in response to denervation in mice Priyanka Sundaram 1, Zhiyu Pang 2, Miao Miao 1, Nathalie Bedard 2, Tamara Moore 2, Patricia L. Hallauer 3, Kenneth E. Hastings 3, Simon S. Wing 2 1 Department of Biochemistry, McGill University, Montreal, QC, Canada; 2 Department of Medicine, McGill University, Montreal, QC, Canada; 3 Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada Background and aims : Although many enzymes involved in ubiquitination are activated in atrophying muscle, little is known about the role of deubiquitinating enzymes (DUBs).
USP19 affects Ubiquitin
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USP19 inhibits Ubiquitin.
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RNF216 interacts with and ubiquitinates Beclin 1 at lysine 48, thereby contributing to Beclin 1 degradation, while SLC9A3R1 and USP19 blocks ubiquitin dependent Beclin 1 degradation by interacting with Beclin 1 and removing the K11 linked ubiquitin respectively.
USP19 activates Ubiquitin.
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The interaction of USP19 with substrates causes the removal of ubiquitin chains, which facilitates the export of MAPS substrates 3.
USP19 affects MAPT
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USP19 inhibits MAPT.
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USP19 inhibits MAPT. 1 / 1
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The results confirmed that DNAJC5 stimulated Tau secretion was not reduced by depletion of USP19.
USP19 activates MAPT.
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USP19 activates MAPT. 1 / 1
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USP19 CT incrementUI also stimulated GFP1-10 and Tau secretion.
USP19 affects DNAJC5
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USP19 inhibits DNAJC5.
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USP19 inhibits DNAJC5. 1 / 1
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If so, depletion of USP19 should abolish DNAJC5 stimulated secretion.
USP19 activates DNAJC5.
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USP19-C506S activates DNAJC5. 1 / 1
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Moreover, we found that WT USP19 but not USP19 C506S also enhanced DNAJC5 secretion, consistent with the idea that when USP19 induced MAPS, DNAJC5 accompanied substrates to the cell exterior.
SIAH2 affects USP19
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SIAH2 inhibits USP19.
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SIAH2 inhibits USP19. 1 / 1
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The expression levels of Myc-USP19 Delta462-473 remained constant in spite of SIAH overexpression while Myc-USP19 was efficiently degraded, confirming that the SIAH binding motif is required for USP19[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
SIAH2 decreases the amount of USP19.
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Modified SIAH2 decreases the amount of USP19. 1 / 1
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Co-expression of functional SIAH1 or SIAH2 dramatically decreased the expression levels of Myc-USP19, while the expression was rescued by in treatment with MG132, suggesting that both SIAHs target USP[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
SIAH1 affects USP19
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SIAH1 inhibits USP19.
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SIAH1 inhibits USP19. 1 / 1
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The expression levels of Myc-USP19 Delta462-473 remained constant in spite of SIAH overexpression while Myc-USP19 was efficiently degraded, confirming that the SIAH binding motif is required for USP19[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
SIAH1 decreases the amount of USP19.
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Modified SIAH1 decreases the amount of USP19. 1 / 1
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Co-expression of functional SIAH1 or SIAH2 dramatically decreased the expression levels of Myc-USP19, while the expression was rescued by in treatment with MG132, suggesting that both SIAHs target USP[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
DNAJC5 affects USP19
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DNAJC5 increases the amount of USP19.
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DNAJC5 increases the amount of USP19. 1 / 1
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Although DNAJC5 knockdown reduced the expression of USP19 by ~ 30%, this was unlikely to account for the difference in MAPS efficiency between control and DNAJC5 knockdown cells for the following reasons.
DNAJC5 activates USP19.
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DNAJC5 activates USP19. 1 / 1
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Overexpression of DNAJC5 promotes MAPS independently of USP19.
Vinclozolin affects USP19
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Vinclozolin decreases the amount of USP19. 1 / 1
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ctd
No evidence text available
Tungsten affects USP19
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Tungsten decreases the amount of USP19. 1 / 1
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ctd
No evidence text available
Sunitinib affects USP19
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Sunitinib decreases the amount of USP19. 1 / 1
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No evidence text available
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Sodium arsenite increases the amount of USP19. 1 / 1
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ctd
No evidence text available
Phlorizin affects USP19
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Phlorizin increases the amount of USP19. 1 / 1
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ctd
No evidence text available
Paracetamol affects USP19
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Paracetamol increases the amount of USP19. 1 / 1
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ctd
No evidence text available
Methyl methanesulfonate increases the amount of USP19. 1 / 1
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ctd
No evidence text available
Melatonin affects USP19
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Melatonin increases the amount of USP19. 1 / 1
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Table 2. Genes showing melatonin-induced upregulation in peripheral blood mononuclear cell
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Hsa-miR-615-3p decreases the amount of USP19. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-196a-5p decreases the amount of USP19. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-186-5p decreases the amount of USP19. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-183-5p decreases the amount of USP19. 1 / 1
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biopax:mirtarbase
No evidence text available
Hexabromocyclododecane increases the amount of USP19. 1 / 1
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No evidence text available
Estradiol affects USP19
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Estradiol increases the amount of USP19. 1 / 1
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It is shown that estradiol can induce expression of USP19 and with the above mentioned mechanism can repress myotube formation XREF_BIBR.
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ctd
No evidence text available
Copper atom affects USP19
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Copper atom increases the amount of USP19. 1 / 1
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No evidence text available
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Beta-carotene decreases the amount of USP19. 1 / 1
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In the denervated soleus muscle, beta-carotene administration significantly decreased the expression levels of Atrogin-1, MuRF1, USP14 and USP19 (P < 0.05, n 5) and the levels of ubiquitin conjugates.
Atrazine affects USP19
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Atrazine increases the amount of USP19. 1 / 1
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No evidence text available
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Aflatoxin B1 increases the amount of USP19. 1 / 1
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No evidence text available
Acrylamide affects USP19
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Acrylamide increases the amount of USP19. 1 / 1
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No evidence text available

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Furthermore, USP19 deficiency in macrophages caused an elevation of TBK1 and the activation of the type-I interferon signaling pathway after vesicular stomatitis virus (VSV) infection.
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We therefore tested whether USP19 modulates this differentiation dependent CHOP induction and, if so, whether it requires ER localization.
USP19 affects glucose
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USP19 activates glucose. 1 / 1
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The deubiquitinating enzyme USP19 modulates adipogenesis and potentiates high-fat-diet-induced obesity and glucose intolerance in mice.
USP19 affects ges-1
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USP19 activates ges-1. 1 / 1
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Transwell assay showed that knockdown of USP19 decreased invasiveness of SGC7901 cells, whereas overexpression of USP19 enhanced GES1 cell invasion (P < 0.01; XREF_FIG and XREF_FIG, respectively).

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Under these conditions, cell viability was unaffected and ER stress was not induced by USP19 knockdown.
USP19 affects dioxygen
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USP19 inhibited NLRP3 inflammasome activation by increasing autophagy flux and decreasing the generation of mitochondrial reactive oxygen species.
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Depletion of USP19 reversed the dexamethasone suppression of MHC.

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The chromosome segregation errors induced by USP19 knockdown was reversed by the expression of siRNA resistant wild-type USP19.
USP19 affects USP19
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Modified USP19 decreases the amount of USP19. 1 / 1
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Overexpression of USP19 inhibited RARE transcription and knock-down of USP19 using siRNA showed dramatically increased transcription of RARE, suggesting that USP19 increases the stability of CORO2A by DUB activity, and that binding of these two protein may be associated with the function of NCoR.
USP19 affects TRIM69
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USP19 activates TRIM69. 1 / 1
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However, USP13, USP19, and USP22 inhibit virus-induced IFN production by removing K27-linked polyubiquitin chains from STING (40, 81) or TRIF (90).
USP19 affects TRAF3
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USP19 activates TRAF3. 1 / 1
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USP19 suppresses cellular type I interferon signaling by targeting TRAF3 for deubiquitination.
USP19 affects RARS1
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USP19 activates RARS1. 1 / 1
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Therefore, we hypothesized that USP19, which was found to bind with CORO2A, may mediate the function of the RARs via transcriptional repression of RARE.
USP19 affects Neoplasms
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Moreover, the downregulation of USP19 promoted tumor growth in a xenograft model.
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USP19 affects NR3C1
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USP19 increases the amount of NR3C1. 1 / 1
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Thus, USP19 modulates GR levels and in so doing may modulate both insulin and glucocorticoid signaling, two critical pathways that control protein turnover in muscle and overall glucose homeostasis.
USP19 affects NFkappaB
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So an attractive hypothesis is that USP19 might promote muscle atrophy by stabilizing cIAPs and activating the NFkappaB pathway.
USP19 affects MYH
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USP19 inhibits MYH. 1 / 1
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They found that a decrease of USP19 promoted muscle cell fusion and increased myotube diameter and expressions of myogenin and myosin heavy chain.
USP19 affects MARCHF7
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USP19 activates MARCHF7. 1 / 1
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Furthermore, DUBs are known to regulate stability of only 4 of these proteins, including the ubiquitin ligases MARCH7 and BIRC3, which are targeted by USP7 or USP9 and USP19, respectively.
USP19 affects INS
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USP19 activates INS. 1 / 1
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Moreover, HFD fed Usp19 -/- mice had enhanced insulin signalling in the muscle and the liver, but not in adipose tissue.

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As to its essential role in DNA repair and in maintaining chromosome stability, USP19 might be critical for cells to prevent genome instability and its deletion might be contributed to tumorigenesis.
USP19 affects FLVCR1
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USP19 activates FLVCR1. 1 / 1
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Reports indicate that the disruption of USP19 inhibits a series of PCa cell proliferation by arresting cells in the G1 to S phase transition through stabilization of the cyclin-dependent kinase inhibitor p27 .
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USP19 affects DDX58