TISIDB

Summary
Symbol	USP15
Name	ubiquitin specific peptidase 15
Aliases	KIAA0529; UNPH4; ubiquitin specific protease 15; UNPH-2; deubiquitinating enzyme 15; ubiquitin thioesterase ......
Chromosomal Location	12q14
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cytoplasm Nucleus Mitochondrion
Domain	PF06337 DUSP domain PF14836 Ubiquitin-like domain PF00443 Ubiquitin carboxyl-terminal hydrolase PF14533 Ubiquitin-specific protease C-terminal
Function	Hydrolase that removes conjugated ubiquitin from target proteins and regulates various pathways such as the TGF-beta receptor signaling, NF-kappa-B and RNF41/NRDP1-PRKN pathways (PubMed:21947082, PubMed:22344298, PubMed:24852371, PubMed:16005295, PubMed:17318178, PubMed:19826004, PubMed:19576224). Acts as a key regulator of TGF-beta receptor signaling pathway, but the precise mechanism is still unclear: according to a report, acts by promoting deubiquitination of monoubiquitinated R-SMADs (SMAD1, SMAD2 and/or SMAD3), thereby alleviating inhibition of R-SMADs and promoting activation of TGF-beta target genes (PubMed:21947082). According to another reports, regulates the TGF-beta receptor signaling pathway by mediating deubiquitination and stabilization of TGFBR1, leading to an enhanced TGF-beta signal (PubMed:22344298). Able to mediate deubiquitination of monoubiquitinated substrates as well as 'Lys-48'-linked polyubiquitin chains, protecting them against proteasomal degradation. May also regulate gene expression and/or DNA repair through the deubiquitination of histone H2B (PubMed:24526689). Acts as an inhibitor of mitophagy by counteracting the action of parkin (PRKN): hydrolyzes cleavage of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains attached by parkin on target proteins such as MFN2, thereby reducing parkin's ability to drive mitophagy (PubMed:24852371). Acts as an associated component of COP9 signalosome complex (CSN) and regulates different pathways via this association: regulates NF-kappa-B by mediating deubiquitination of NFKBIA and deubiquitinates substrates bound to VCP (PubMed:16005295, PubMed:17318178, PubMed:19826004, PubMed:19576224). Involved in endosome organization by mediating deubiquitination of SQSTM1: ubiquitinated SQSTM1 forms a molecular bridge that restrains cognate vesicles in the perinuclear region and its deubiquitination releases target vesicles for fast transport into the cell periphery (PubMed:27368102). ; FUNCTION: (Microbial infection) Protects APC and human papillomavirus type 16 protein E6 against degradation via the ubiquitin proteasome pathway.

> Gene Ontology [ TOP ]
Biological Process	GO:0007178 transmembrane receptor protein serine/threonine kinase signaling pathway GO:0007179 transforming growth factor beta receptor signaling pathway GO:0016570 histone modification GO:0016578 histone deubiquitination GO:0016579 protein deubiquitination GO:0030509 BMP signaling pathway GO:0035520 monoubiquitinated protein deubiquitination GO:0035616 histone H2B conserved C-terminal lysine deubiquitination GO:0060389 pathway-restricted SMAD protein phosphorylation GO:0070646 protein modification by small protein removal GO:0071559 response to transforming growth factor beta GO:0071560 cellular response to transforming growth factor beta stimulus GO:0071772 response to BMP GO:0071773 cellular response to BMP stimulus
Molecular Function	GO:0004175 endopeptidase activity GO:0004197 cysteine-type endopeptidase activity GO:0004843 thiol-dependent ubiquitin-specific protease activity GO:0005126 cytokine receptor binding GO:0005160 transforming growth factor beta receptor binding GO:0008234 cysteine-type peptidase activity GO:0019783 ubiquitin-like protein-specific protease activity GO:0036459 thiol-dependent ubiquitinyl hydrolase activity GO:0042393 histone binding GO:0046332 SMAD binding GO:0061649 ubiquitinated histone binding GO:0101005 ubiquitinyl hydrolase activity
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	-
Reactome	R-HSA-5688426: Deubiquitination R-HSA-2173788: Downregulation of TGF-beta receptor signaling R-HSA-392499: Metabolism of proteins R-HSA-597592: Post-translational protein modification R-HSA-162582: Signal Transduction R-HSA-170834: Signaling by TGF-beta Receptor Complex R-HSA-2173789: TGF-beta receptor signaling activates SMADs R-HSA-5689603: UCH proteinases R-HSA-5689880: Ub-specific processing proteases

> KEGG and Reactome Pathway

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KEGG

Reactome

R-HSA-5688426: Deubiquitination
R-HSA-2173788: Downregulation of TGF-beta receptor signaling
R-HSA-392499: Metabolism of proteins
R-HSA-597592: Post-translational protein modification
R-HSA-162582: Signal Transduction
R-HSA-170834: Signaling by TGF-beta Receptor Complex
R-HSA-2173789: TGF-beta receptor signaling activates SMADs
R-HSA-5689603: UCH proteinases
R-HSA-5689880: Ub-specific processing proteases

Summary
Symbol	USP15
Name	ubiquitin specific peptidase 15
Aliases	KIAA0529; UNPH4; ubiquitin specific protease 15; UNPH-2; deubiquitinating enzyme 15; ubiquitin thioesterase ......
Chromosomal Location	12q14
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between USP15 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between USP15 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
24777531	Melanoma; Colon Carcinoma	Inhibit immunity (T cell function)	Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival.

Summary
Symbol	USP15
Name	ubiquitin specific peptidase 15
Aliases	KIAA0529; UNPH4; ubiquitin specific protease 15; UNPH-2; deubiquitinating enzyme 15; ubiquitin thioesterase ......
Chromosomal Location	12q14
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of USP15 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	USP15
Name	ubiquitin specific peptidase 15
Aliases	KIAA0529; UNPH4; ubiquitin specific protease 15; UNPH-2; deubiquitinating enzyme 15; ubiquitin thioesterase ......
Chromosomal Location	12q14
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of USP15 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	-0.052	0.86
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.008	0.996
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.075	0.94
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.276	0.401
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.403	0.862
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.118	0.967
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.035	0.93
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.112	0.948
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.022	0.99
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.49	0.732
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.581	0.79
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.014	0.801

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of USP15 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	3.7	1.4	2.3	0.469
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	1.7	2	0.532
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	9.5	0	9.5	0.492
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	12.5	0	12.5	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	7.7	0	7.7	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	6.2	-6.2	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	11.1	-11.1	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	USP15
Name	ubiquitin specific peptidase 15
Aliases	KIAA0529; UNPH4; ubiquitin specific protease 15; UNPH-2; deubiquitinating enzyme 15; ubiquitin thioesterase ......
Chromosomal Location	12q14
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of USP15. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	USP15
Name	ubiquitin specific peptidase 15
Aliases	KIAA0529; UNPH4; ubiquitin specific protease 15; UNPH-2; deubiquitinating enzyme 15; ubiquitin thioesterase ......
Chromosomal Location	12q14
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of USP15. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by USP15. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	USP15
Name	ubiquitin specific peptidase 15
Aliases	KIAA0529; UNPH4; ubiquitin specific protease 15; UNPH-2; deubiquitinating enzyme 15; ubiquitin thioesterase ......
Chromosomal Location	12q14
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of USP15. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	USP15
Name	ubiquitin specific peptidase 15
Aliases	KIAA0529; UNPH4; ubiquitin specific protease 15; UNPH-2; deubiquitinating enzyme 15; ubiquitin thioesterase ......
Chromosomal Location	12q14
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of USP15 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	USP15
Name	ubiquitin specific peptidase 15
Aliases	KIAA0529; UNPH4; ubiquitin specific protease 15; UNPH-2; deubiquitinating enzyme 15; ubiquitin thioesterase ......
Chromosomal Location	12q14
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between USP15 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	USP15
Name	ubiquitin specific peptidase 15
Aliases	KIAA0529; UNPH4; ubiquitin specific protease 15; UNPH-2; deubiquitinating enzyme 15; ubiquitin thioesterase ......
Chromosomal Location	12q14
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting USP15 collected from DrugBank database.

> Drugs from DrugBank database [ TOP ]
There is no record.

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