USP15

Summary

USP15 (ubiquitin specific peptidase 15, HGNC:12613) is a protein-coding gene on chromosome 12q14.1, encoding Ubiquitin carboxyl-terminal hydrolase 15 (Q9Y4E8). 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.

This gene encodes a member of the ubiquitin specific protease (USP) family of deubiquitinating enzymes. USP enzymes play critical roles in ubiquitin-dependent processes through polyubiquitin chain disassembly and hydrolysis of ubiquitin-substrate bonds. The encoded protein associates with the COP9 signalosome, and also plays a role in transforming growth factor beta signalling through deubiquitination of receptor-activated SMAD transcription factors. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 2.

Source: NCBI Gene 9958 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 93 total
• Druggable target: yes
• MANE Select transcript: NM_001252078

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12613
Approved symbol	USP15
Name	ubiquitin specific peptidase 15
Location	12q14.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0529, UNPH4
Ensembl gene	ENSG00000135655
Ensembl biotype	protein_coding
OMIM	604731
Entrez	9958

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 18 protein_coding, 5 protein_coding_CDS_not_defined, 4 retained_intron, 2 nonsense_mediated_decay

ENST00000280377, ENST00000312635, ENST00000353364, ENST00000537297, ENST00000546694, ENST00000546718, ENST00000547317, ENST00000548524, ENST00000548620, ENST00000548836, ENST00000549101, ENST00000549237, ENST00000549268, ENST00000549415, ENST00000549523, ENST00000550632, ENST00000551206, ENST00000552346, ENST00000552997, ENST00000886867, ENST00000886868, ENST00000886869, ENST00000913305, ENST00000957645, ENST00000957646, ENST00000957647, ENST00000957648, ENST00000957649, ENST00000957650

RefSeq mRNA: 11 — MANE Select: NM_001252078 NM_001252078, NM_001252079, NM_001351159, NM_001351160, NM_001351161, NM_001351162, NM_001351163, NM_001351164, NM_001351165, NM_001351166, NM_006313

CCDS: CCDS58250, CCDS58251, CCDS8963

Canonical transcript exons

ENST00000280377 — 22 exons

Exon	Start	End
ENSE00000937164	62383840	62383998
ENSE00000937165	62384078	62384302
ENSE00000937168	62389797	62389988
ENSE00000937169	62390864	62390979
ENSE00000937170	62391157	62391429
ENSE00000937171	62391816	62391886
ENSE00000937172	62392272	62392387
ENSE00000937173	62393053	62393202
ENSE00000937174	62396295	62396398
ENSE00000996340	62349221	62349307
ENSE00001358543	62404193	62416389
ENSE00002377734	62260404	62260503
ENSE00003479566	62389431	62389514
ENSE00003503683	62381490	62381663
ENSE00003504640	62314790	62314916
ENSE00003509743	62321464	62321609
ENSE00003517155	62401187	62401275
ENSE00003535784	62294179	62294306
ENSE00003546241	62355331	62355475
ENSE00003561631	62302790	62302920
ENSE00003601585	62389605	62389699
ENSE00003788827	62325872	62325933

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.15.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2718 / max 33.9493, expressed in 721 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126382	62.4437	1819
126381	1.2718	721

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.15	gold quality
mononuclear cell	CL:0000842	99.10	gold quality
leukocyte	CL:0000738	99.04	gold quality
calcaneal tendon	UBERON:0003701	99.00	gold quality
granulocyte	CL:0000094	98.29	gold quality
right lung	UBERON:0002167	98.08	gold quality
bone marrow cell	CL:0002092	97.74	gold quality
right testis	UBERON:0004534	97.67	gold quality
blood	UBERON:0000178	97.62	gold quality
left testis	UBERON:0004533	97.60	gold quality
adrenal tissue	UBERON:0018303	97.59	gold quality
spleen	UBERON:0002106	97.44	gold quality
bone marrow	UBERON:0002371	97.20	gold quality
skin of abdomen	UBERON:0001416	97.05	gold quality
skin of leg	UBERON:0001511	96.98	gold quality
triceps brachii	UBERON:0001509	96.85	gold quality
mucosa of stomach	UBERON:0001199	96.83	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.79	gold quality
upper lobe of left lung	UBERON:0008952	96.65	gold quality
trabecular bone tissue	UBERON:0002483	96.63	gold quality
vermiform appendix	UBERON:0001154	96.54	gold quality
left ovary	UBERON:0002119	96.54	gold quality
lower esophagus mucosa	UBERON:0035834	96.51	gold quality
right lobe of liver	UBERON:0001114	96.43	gold quality
body of pancreas	UBERON:0001150	96.40	gold quality
biceps brachii	UBERON:0001507	96.36	gold quality
rectum	UBERON:0001052	96.34	gold quality
gluteal muscle	UBERON:0002000	96.32	gold quality
tibial nerve	UBERON:0001323	96.25	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.24	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.38
E-GEOD-110499	no	1242.85
E-MTAB-6678	no	3.53
E-HCAD-10	no	2.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

243 targeting USP15, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817

Literature-anchored findings (GeneRIF, showing 40)

• A functional Zn finger of USP15 is needed to maintain a conformation essential for disassembling poly-Ub chains, a prerequisite for rescuing the E3 ligase Rbx1. (PMID:16005295)
• analysis of the human ubiquitin-specific protease 15 DUSP domain (PMID:16298993)
• These results implicate USP15 directly in the regulation of E6 protein stability and suggest that ubiquitylated E6 could be a substrate for USP15 ubiquitin peptidase activity. (PMID:19553310)
• Results suggest a role of COP9 signalosome (CSN)-mediated deneddylation in the formation of the beta-catenin-degrading supercomplex and the protection of complex-bound adenomatous polyposis coli via CSN-associated USP15. (PMID:19576224)
• These results indicate that USP15 is involved in the regulation of hypertrophic responses in cardiac muscle through transcriptional and post-translational modulation of SLIM1. (PMID:21219870)
• A 1.5 A resolution crystal structure of the human USP15 N-terminal domain revealed a 80 A elongated arrangement with the domains aligned in tandem. (PMID:21848306)
• USP15 is critical for the occupancy of endogenous target promoters by the SMAD complex. (PMID:21947082)
• structure of the double domain from USP15 (PMID:22001210)
• Our results show that USP15 regulates the TGF-beta pathway and is a key factor in glioblastoma pathogenesis (PMID:22344298)
• The dominant effect of prolonged USP15 depletion upon signal amplitude is due to a decrease in CRAF levels while allowing for the possibility that USP15 may also function to dampen MAPK signaling through direct stabilization of BRAP. (PMID:23105109)
• The deubiquitylase USP15 stabilizes newly synthesized REST and rescues its expression at mitotic exit. (PMID:23708518)
• USP15 specifically deubiquitinates Keap1, which suppresses the Nrf2 pathway. (PMID:23727018)
• Data indicate ubiquitin-specific protease 15 (USP15) as a critical regulator of the tripartite motif protein 25 (TRIM25)- and RNA sensor retinoic acid-inducible gene-I (RIG-I)-mediated antiviral immune response. (PMID:24399297)
• SART3 recruits ubH2B, which may be evicted from DNA during transcription, for deubiquitination by Usp15 (PMID:24526689)
• USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. (PMID:24777531)
• Data show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. (PMID:24850914)
• These data identify USP15 as an antagonist of Parkin and suggest that USP15 inhibition could be a therapeutic strategy for PD cases caused by reduced Parkin levels. (PMID:24852371)
• Data suggest that ubiquitin specific peptidase 15 (USP15) may play a role in the pathogenesis of psoriasis through regulating the type I TGFbeta receptor (TbetaR-I)/Smad7 pathway. (PMID:24939309)
• our data demonstrate that USP15 acts as a negative regulator of RIG-I signaling via DUB-dependent and independent mechanisms. (PMID:26061460)
• SMURF2 is a critical target of USP15 in the TGF-beta signaling pathway. (PMID:26435193)
• crystal structures of SART3 in the apo-form and in complex with the DUSP-UBL domain of USP15 at 2.0 and 3.0 A, respectively. Structural analysis reveals SART3 contains 12 half-a-tetratricopeptide (HAT) repeats, organized into two subdomains, HAT-N and HAT-C. SART3 dimerizes through the concave surface of HAT-C, whereas the HAT-C convex surface binds USP15 in a novel bipartite mode. (PMID:27255711)
• These results uncover a new regulatory mechanism that USP15 activates Nrf1 against the beta-TrCP inhibition to maintain proteostasis. (PMID:27416755)
• these data indicate that Nef and USP15 are vital in regulating degradation of viral and cellular proteins and thus HIV-1 replication, and specific degradation of viral, not cellular proteins. (PMID:27460547)
• TGF-b promotes the translation of USP15 through activation of mammalian target of rapamycin by the phosphoinositide 3-kinase/AKT pathway. Upregulation of USP15 translation links the crosstalk between TGF-beta signaling and p53 stability, allowing this cytokine to have a critical role in cancer progression. (PMID:27893708)
• Deubiquitylation of hepatitis B virus X protein (HBx) by ubiquitin-specific peptidase 15 (USP15) increases HBx stability and its transactivation activity. These results suggest that USP15 plays an essential role in stabilizing HBx and subsequently affects the biological function of HBx. (PMID:28074857)
• We show that PRP31, a component of U4 snRNP, is modified with K63-linked ubiquitin chains by the PRP19 complex and deubiquitinated by USP15 and its substrate targeting factor SART3. USP15SART3 makes a complex with USP4 and this ternary complex serves as a platform to deubiquitinate PRP31 and PRP3 (PMID:28088760)
• We concluded that USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination. (PMID:28126338)
• Data indicate that mysterin/RNF213 is a substrate of ubiquitin specific protease 15 (USP15), and that the conserved skipping of exon 7 significantly decreases its specific affinity for mysterin. (PMID:28276505)
• Study identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent de novo variants (FOXP1 and KDM5B). (PMID:28344757)
• HPV E6 oncoprotein antagonizes the activation of the cytoplasmic innate immune sensor RIG-I by targeting its upstream regulatory enzymes TRIM25 and USP15. We further show that the RIG-I signaling cascade is important for an antiviral innate immune response to HPV16 infection (PMID:29263274)
• First example of isoform-specific deubiquitylase phospho-regulation and a novel role for USP15 in guarding genome integrity. USP15 is required for TOP2A accumulation, and USP15 depletion leads to the formation of anaphase chromosome bridges. (PMID:29429988)
• a USP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells (PMID:29593334)
• USP15 could increase the level of HPV16 E6 by inhibiting E6 degradation. (PMID:29895155)
• USP15 participates in HCV propagation in hepatic cells. (PMID:30626683)
• The molecular structure of USP15 and its ubiquitin variant inhibitors has been reported. (PMID:30713027)
• Study reports that USP15 affects cancer cell response to PARP inhibitors by regulating homologous recombination repair. USP15 is recruited to DNA double-strand breaks (DSBs) by MDC1. USP15 deubiquitinates BARD1 BRCT domain, and promotes BARD1-HP1gamma interaction, resulting in BRCA1/BARD1 retention at DSBs. Cancer-associated USP15 mutations, with decreased USP15-BARD1 interaction, increases PARP inhibitor sensitivity. (PMID:30874560)
• modifications of USP15 and USP4 by phosphorylation are important for the regulation of their localization required for cellular function in the spliceosome. (PMID:31330151)
• TIFAB Regulates USP15-Mediated p53 Signaling during Stressed and Malignant Hematopoiesis. (PMID:32101751)
• Clinicopathological and prognostic significance of ubiquitin-specific peptidase 15 and its relationship with transforming growth factor-beta receptors in patients with pancreatic ductal adenocarcinoma. (PMID:32875609)
• USP15 Deubiquitinates CARD9 to Downregulate C-Type Lectin Receptor-Mediated Signaling. (PMID:33093067)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Usp15	ENSMUSG00000020124
rattus_norvegicus	Usp15	ENSRNOG00000023202

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), USP10 (ENSG00000103194), USP31 (ENSG00000103404), USP42 (ENSG00000106346), USP5 (ENSG00000111667), USP4 (ENSG00000114316), USP9Y (ENSG00000114374), USP34 (ENSG00000115464), USP35 (ENSG00000118369), USP45 (ENSG00000123552), USP22 (ENSG00000124422), USP9X (ENSG00000124486), USP6 (ENSG00000129204), USP29 (ENSG00000131864), USP26 (ENSG00000134588), USP30 (ENSG00000135093), USP37 (ENSG00000135913), USP44 (ENSG00000136014), USP20 (ENSG00000136878), USP8 (ENSG00000138592), USP3 (ENSG00000140455), USP21 (ENSG00000143258), USP43 (ENSG00000154914), USP25 (ENSG00000155313), USP16 (ENSG00000156256), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242), USP32 (ENSG00000170832)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 15 — Q9Y4E8 (reviewed: Q9Y4E8)

Alternative names: Deubiquitinating enzyme 15, Ubiquitin thioesterase 15, Ubiquitin-specific-processing protease 15, Unph-2, Unph4

All UniProt accessions (8): Q9Y4E8, F8VVY7, F8VZG8, F8W0H4, H0YH96, H0YHM4, H0YI26, H0YI31

UniProt curated annotations — full annotation on UniProt →

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. 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. 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. Able to mediate deubiquitination of monoubiquitinated substrates, ‘Lys-27’-, ‘Lys-48’- and ‘Lys-63’-linked polyubiquitin chains. May also regulate gene expression and/or DNA repair through the deubiquitination of histone H2B. 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. 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. 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. Acts as a negative regulator of antifungal immunity by mediating ‘Lys-27’-linked deubiquitination of CARD9, thereby inactivating CARD9. (Microbial infection) Protects APC and human papillomavirus type 16 protein E6 against degradation via the ubiquitin proteasome pathway.

Subunit / interactions. A homodimer structure has been reported; however it is unclear whether the protein form a homodimer in vivo. Identified in a complex with the COP9 signalosome complex (CSN). Interacts with SMAD1, SMAD2 and SMAD3; the interaction is direct. Forms a complex with SMURF2 and SMAD7. Interacts with TGFBR1. Interacts with SART3; the interaction is direct. May interact with RNF20 and RNF40. May interact with PRKN. Interacts with INCA1. (Microbial infection) Interacts with human papillomavirus type 16 protein E6.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion.

Tissue specificity. Expressed in skeletal muscle, kidney, heart, placenta, liver, thymus, lung, and ovary, with little or no expression in other tissues.

Post-translational modifications. Phosphorylated. Phosphorylation protects against ubiquitination and subsequent degradation by the proteasome. Ubiquitinated, leading to degradation by the proteasome.

Similarity. Belongs to the peptidase C19 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y4E8-1	1	yes
Q9Y4E8-2	2
Q9Y4E8-3	3
Q9Y4E8-4	4

RefSeq proteins (9): NP_001239007, NP_001239008, NP_001338088, NP_001338089, NP_001338092, NP_001338093, NP_001338094, NP_001338095, NP_006304 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR006615	Pept_C19_DUSP	Domain
IPR013792	RNA3’P_cycl/enolpyr_Trfase_a/b	Homologous_superfamily
IPR018200	USP_CS	Conserved_site
IPR028135	Ub_USP-typ	Domain
IPR028889	USP	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR029346	USP_C	Domain
IPR035927	DUSP-like_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050185	Ub_carboxyl-term_hydrolase	Family

Pfam: PF00443, PF06337, PF14533, PF14836

UniProt features (91 total): strand 33, helix 22, modified residue 7, turn 7, splice variant 4, region of interest 4, compositionally biased region 3, sequence conflict 3, active site 2, domain 2, mutagenesis site 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
4A3P	X-RAY DIFFRACTION	1.4
3T9L	X-RAY DIFFRACTION	1.5
6ML1	X-RAY DIFFRACTION	1.9
6GHA	X-RAY DIFFRACTION	1.98
7R2G	X-RAY DIFFRACTION	1.98
6CPM	X-RAY DIFFRACTION	2.01
6GH9	X-RAY DIFFRACTION	2.09
3LMN	X-RAY DIFFRACTION	2.15
4A3O	X-RAY DIFFRACTION	2.2
3PPA	X-RAY DIFFRACTION	2.35
6CRN	X-RAY DIFFRACTION	2.5
3PV1	X-RAY DIFFRACTION	2.6
5JJW	X-RAY DIFFRACTION	3.01
6DJ9	X-RAY DIFFRACTION	3.1
1W6V	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4E8-F1	76.16	0.44

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 298 (nucleophile); 891 (proton acceptor)

Post-translational modifications (7): 2, 226, 229, 242, 602, 961, 965

Mutagenesis-validated functional residues (2):

Position	Phenotype
298	loss of enzyme activity.
812	loss of activity towards polyubiquitin.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2173788	Downregulation of TGF-beta receptor signaling
R-HSA-5689603	UCH proteinases
R-HSA-5689880	Ub-specific processing proteases

MSigDB gene sets: 395 (showing top): MYAATNNNNNNNGGC_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, ACTACCT_MIR196A_MIR196B, TAATAAT_MIR126, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, TGCACTT_MIR519C_MIR519B_MIR519A, GCANCTGNY_MYOD_Q6, AREB6_03, AAGCCAT_MIR135A_MIR135B, DITTMER_PTHLH_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, RIZKI_TUMOR_INVASIVENESS_3D_DN

GO Biological Process (13): proteolysis (GO:0006508), transforming growth factor beta receptor signaling pathway (GO:0007179), protein deubiquitination (GO:0016579), BMP signaling pathway (GO:0030509), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), monoubiquitinated protein deubiquitination (GO:0035520), regulation of RNA metabolic process (GO:0051252), transcription elongation-coupled chromatin remodeling (GO:0140673), positive regulation of RIG-I signaling pathway (GO:1900246), regulation of intrinsic apoptotic signaling pathway in response to osmotic stress by p53 class mediator (GO:1902238), negative regulation of antifungal innate immune response (GO:1905035), protein K27-linked deubiquitination (GO:1990167), positive regulation of canonical NF-kappaB signal transduction (GO:0043123)

GO Molecular Function (13): cysteine-type endopeptidase activity (GO:0004197), cysteine-type deubiquitinase activity (GO:0004843), transforming growth factor beta receptor binding (GO:0005160), identical protein binding (GO:0042802), SMAD binding (GO:0046332), ubiquitin-modified histone reader activity (GO:0061649), deubiquitinase activity (GO:0101005), K48-linked deubiquitinase activity (GO:1990380), catalytic activity (GO:0003824), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), nuclear body (GO:0016604)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Deubiquitination	2
TGF-beta receptor signaling activates SMADs	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
transforming growth factor beta receptor superfamily signaling pathway	2
protein deubiquitination	2
positive regulation of intracellular signal transduction	2
cysteine-type peptidase activity	2
deubiquitinase activity	2
protein binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
protein metabolic process	1
cellular response to transforming growth factor beta stimulus	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
RNA metabolic process	1
regulation of nucleobase-containing compound metabolic process	1
regulation of macromolecule metabolic process	1
chromatin remodeling	1
transcription elongation by RNA polymerase II	1
RIG-I signaling pathway	1
regulation of RIG-I signaling pathway	1
positive regulation of pattern recognition receptor signaling pathway	1
regulation of intrinsic apoptotic signaling pathway in response to osmotic stress	1
regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1
intrinsic apoptotic signaling pathway in response to osmotic stress by p53 class mediator	1
negative regulation of innate immune response	1
antifungal innate immune response	1
regulation of antifungal innate immune response	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
endopeptidase activity	1
cytokine receptor binding	1
ubiquitin-modified protein reader activity	1
histone reader activity	1
ubiquitin-like protein peptidase activity	1
molecular_function	1
binding	1

Protein interactions and networks

STRING

2494 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP15	SMURF2	Q9HAU4	945
USP15	SART3	Q15020	940
USP15	SMAD7	O15105	804
USP15	TRIM25	Q14258	763
USP15	COPS5	Q92905	761
USP15	ZUP1	Q96AP4	745
USP15	UBE2S	Q16763	721
USP15	MDM2	Q00987	664
USP15	UCHL3	P15374	659
USP15	RNF26	Q9BY78	645
USP15	USP25	Q9UHP3	626
USP15	OTUD7B	Q6GQQ9	625
USP15	CYLD	Q9NQC7	624
USP15	UCHL5	Q9Y5K5	619
USP15	BTRC	Q9Y297	611

IntAct

148 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
UBE2E2	OTUB1	psi-mi:“MI:0914”(association)	0.800
PLK1	SPAG9	psi-mi:“MI:0914”(association)	0.790
SART3	PRPF3	psi-mi:“MI:0914”(association)	0.790
UBE2E2	RNF25	psi-mi:“MI:0914”(association)	0.740
PRPF3	PRPF4	psi-mi:“MI:0914”(association)	0.730
SART3	PRPF4	psi-mi:“MI:0914”(association)	0.730
RHPN1	PODXL	psi-mi:“MI:0914”(association)	0.690
SPDL1	USP15	psi-mi:“MI:0915”(physical association)	0.670
CARD9	USP15	psi-mi:“MI:0915”(physical association)	0.670
USP15	SPDL1	psi-mi:“MI:0915”(physical association)	0.670
USP15	CARD9	psi-mi:“MI:0915”(physical association)	0.670
SYVN1	USP15	psi-mi:“MI:0915”(physical association)	0.670
SYVN1	USP15	psi-mi:“MI:0407”(direct interaction)	0.670
USP15	SYVN1	psi-mi:“MI:0915”(physical association)	0.670
SYVN1	USP15	psi-mi:“MI:0403”(colocalization)	0.670
USP15	USP15	psi-mi:“MI:0407”(direct interaction)	0.650
USP15	USP15	psi-mi:“MI:0915”(physical association)	0.650
	USP15	psi-mi:“MI:0204”(deubiquitination reaction)	0.620

BioGRID (724): USP15 (Affinity Capture-MS), PLA2G2A (Biochemical Activity), HIST2H2BE (Biochemical Activity), USP15 (Two-hybrid), USP15 (Two-hybrid), SPDL1 (Two-hybrid), CARD9 (Two-hybrid), CCDC57 (Two-hybrid), USP15 (Affinity Capture-RNA), USP15 (Affinity Capture-MS), USP15 (Affinity Capture-MS), USP15 (Affinity Capture-MS), USP15 (Affinity Capture-MS), USP15 (Affinity Capture-MS), USP15 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IB93, A1A5P5, A1Z7K9, A2XDG4, A3AF13, A3KMI0, A6QR55, B2GUZ1, D3ZJ96, F6V6I0, F6Z5C0, F8VPZ3, O22207, P29375, P35123, P51784, Q09879, Q13107, Q14149, Q2HJE4, Q30DN6, Q3UXZ9, Q3V0C5, Q5D006, Q5I043, Q5RCD3, Q5ZID5, Q5ZM45, Q62240, Q6NZP1, Q76LT8, Q80U87, Q80Y84, Q86UV5, Q8BWR4, Q8NFA0, Q8R5C8, Q8R5H1, Q93Y01, Q96RU2

Diamond homologs: A0A0R4IB93, A0JM59, A1CIL1, A1CW53, A2XDG4, A3AF13, A5PN09, A6QNM7, A7Z056, B1WBD7, B2GUZ1, B8NSV5, D3ZJ96, F6Z5C0, O22207, O60079, O94966, Q0CT11, Q0E2F9, Q0VA64, Q13107, Q2HJE4, Q2UUG8, Q3UJD6, Q3V0C5, Q4VSI4, Q5I043, Q5R5Z6, Q5RCD3, Q5ZM45, Q60MK8, Q6A4J8, Q6J1Y9, Q6PAW2, Q6U7I1, Q6ZQ93, Q70CQ2, Q76LT8, Q7JKC3, Q84WU2

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
USP15	“down-regulates activity”	SQSTM1	deubiquitination
BRAP	“down-regulates quantity by destabilization”	USP15	ubiquitination
USP15	“up-regulates quantity by stabilization”	BRAP	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 149 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SPOP-mediated proteasomal degradation of PD-L1(CD274)	8	16.9×	2e-06
Orc1 removal from chromatin	10	16.5×	1e-07
Degradation of AXIN	7	16.1×	1e-05
Degradation of beta-catenin by the destruction complex	10	16.0×	1e-07
Hh mutants are degraded by ERAD	7	15.8×	1e-05
Regulation of activated PAK-2p34 by proteasome mediated degradation	6	15.5×	6e-05
SCF-beta-TrCP mediated degradation of Emi1	7	15.4×	1e-05
Degradation of DVL	7	15.4×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of protein ubiquitination	6	9.1×	6e-03
ubiquitin-dependent protein catabolic process	10	5.3×	4e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	13	4.8×	1e-03
DNA damage response	12	4.6×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

93 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	67
Likely benign	5
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

4181 predictions. Top by Δscore:

Variant	Effect	Δscore
12:62260490:A:T	donor_gain	1.0000
12:62260501:CTGGT:C	donor_loss	1.0000
12:62260503:GGT:G	donor_loss	1.0000
12:62260504:G:GG	donor_gain	1.0000
12:62260504:G:T	donor_loss	1.0000
12:62260505:T:G	donor_loss	1.0000
12:62294174:TTTA:T	acceptor_loss	1.0000
12:62294175:TTAG:T	acceptor_loss	1.0000
12:62294176:TAG:T	acceptor_loss	1.0000
12:62294178:G:A	acceptor_loss	1.0000
12:62294302:CAAAG:C	donor_loss	1.0000
12:62294303:AAAG:A	donor_loss	1.0000
12:62294304:AAGG:A	donor_loss	1.0000
12:62294305:AG:A	donor_loss	1.0000
12:62294306:GG:G	donor_loss	1.0000
12:62294307:G:C	donor_loss	1.0000
12:62294308:T:G	donor_loss	1.0000
12:62294332:GTT:G	donor_gain	1.0000
12:62302784:TTGCA:T	acceptor_loss	1.0000
12:62302785:TGCA:T	acceptor_loss	1.0000
12:62302786:GCA:G	acceptor_loss	1.0000
12:62302787:CA:C	acceptor_loss	1.0000
12:62302788:A:AG	acceptor_gain	1.0000
12:62302788:AGAT:A	acceptor_gain	1.0000
12:62302788:AGATG:A	acceptor_gain	1.0000
12:62302789:G:GT	acceptor_gain	1.0000
12:62302789:GA:G	acceptor_gain	1.0000
12:62302789:GAT:G	acceptor_gain	1.0000
12:62302789:GATG:G	acceptor_gain	1.0000
12:62302789:GATGG:G	acceptor_gain	1.0000

AlphaMissense

6563 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:62294198:T:A	W37R	1.000
12:62294198:T:C	W37R	1.000
12:62294210:T:A	W41R	1.000
12:62294210:T:C	W41R	1.000
12:62294274:C:A	P62H	1.000
12:62302820:T:C	L83P	1.000
12:62302916:G:C	R115P	1.000
12:62314808:T:C	F123L	1.000
12:62314810:T:A	F123L	1.000
12:62314810:T:G	F123L	1.000
12:62321526:T:A	W180R	1.000
12:62321526:T:C	W180R	1.000
12:62325908:T:A	W220R	1.000
12:62325908:T:C	W220R	1.000
12:62355420:G:A	G287D	1.000
12:62355428:G:C	G290R	1.000
12:62355429:G:A	G290D	1.000
12:62355429:G:T	G290V	1.000
12:62355432:T:A	L291Q	1.000
12:62355432:T:C	L291P	1.000
12:62355437:A:G	N293D	1.000
12:62355439:C:A	N293K	1.000
12:62355439:C:G	N293K	1.000
12:62355443:G:A	G295R	1.000
12:62355443:G:C	G295R	1.000
12:62355444:G:A	G295E	1.000
12:62355444:G:T	G295V	1.000
12:62355447:A:T	N296I	1.000
12:62355448:T:A	N296K	1.000
12:62355448:T:G	N296K	1.000

dbSNP variants (sampled 300 via entrez): RS1000008171 (12:62310890 GTTGTCTT>G), RS1000029099 (12:62260261 C>G,T), RS1000030972 (12:62344653 C>T), RS1000050017 (12:62270602 C>G,T), RS1000057941 (12:62266439 A>G), RS1000063139 (12:62351253 G>A,C), RS1000070447 (12:62308592 G>A,T), RS1000080627 (12:62402842 A>G), RS1000104777 (12:62351923 G>A), RS1000109434 (12:62333022 C>T), RS1000136936 (12:62395346 C>T), RS1000139363 (12:62376898 CAT>C), RS1000150115 (12:62373131 C>G,T), RS1000203684 (12:62369668 G>A,T), RS1000204009 (12:62285314 G>A)

Disease associations

OMIM: gene MIM:604731 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001444_4	Pulmonary function decline	7.000000e-06
GCST002379_4	Pyoderma gangrenosum in inflammatory bowel disease	5.000000e-06
GCST004607_49	Plateletcrit	3.000000e-09
GCST004866_20	Alopecia areata	4.000000e-06
GCST009391_1032	Metabolite levels	3.000000e-06
GCST009391_489	Metabolite levels	5.000000e-07
GCST90002400_719	Plateletcrit	3.000000e-16
GCST90002401_46	Platelet distribution width	8.000000e-13

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0006835	pyoderma gangrenosum
EFO:0007985	platelet crit
EFO:0009775	threonine measurement
EFO:0005001	phenylalanine measurement
EFO:0007984	platelet component distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523508 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

2 measured of 4 human assays (5 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Acetyl Isogambogic Acid	IC50	11100 nM
Mangiferin	IC50	56600 nM

CTD chemical–gene interactions

53 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	9
bisphenol A	affects methylation, increases expression, affects cotreatment	3
Phenylmercuric Acetate	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
decabromobiphenyl ether	increases expression	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	affects cotreatment, increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
cupric oxide	increases expression	1
1-nitropyrene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
CTAP octapeptide	decreases reaction, increases expression	1
jinfukang	decreases expression	1
Aspirin	increases expression	1
Benzo(a)pyrene	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4372607	Binding	Inhibition of USP15 in HEK293T cell lysates at 25 uM using HA-tagged vinyl-sulfone as substrate measured after 2 to 30 mins by Western blot analysis	Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TW58	HAP1 USP15 (-) 1	Cancer cell line	Male
CVCL_TW59	HAP1 USP15 (-) 2	Cancer cell line	Male
CVCL_TW60	HAP1 USP15 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.