USP10

Summary

USP10 (ubiquitin specific peptidase 10, HGNC:12608) is a protein-coding gene on chromosome 16q24.1, encoding Ubiquitin carboxyl-terminal hydrolase 10 (Q14694). Hydrolase that can remove conjugated ubiquitin from target proteins such as p53/TP53, RPS2/us5, RPS3/us3, RPS10/eS10, BECN1, SNX3 and CFTR. It is a selective cancer dependency (DepMap: 59.8% of cell lines).

Ubiquitin is a highly conserved protein that is covalently linked to other proteins to regulate their function and degradation. This gene encodes a member of the ubiquitin-specific protease family of cysteine proteases. The enzyme specifically cleaves ubiquitin from ubiquitin-conjugated protein substrates. The protein is found in the nucleus and cytoplasm. It functions as a co-factor of the DNA-bound androgen receptor complex, and is inhibited by a protein in the Ras-GTPase pathway. The human genome contains several pseudogenes similar to this gene. Several transcript variants, some protein-coding and others not protein-coding, have been found for this gene.

Source: NCBI Gene 9100 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 166 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 59.8% of screened cell lines
• MANE Select transcript: NM_005153

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12608
Approved symbol	USP10
Name	ubiquitin specific peptidase 10
Location	16q24.1
Locus type	gene with protein product
Status	Approved
Aliases	UBPO, KIAA0190
Ensembl gene	ENSG00000103194
Ensembl biotype	protein_coding
OMIM	609818
Entrez	9100

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 23 protein_coding, 4 protein_coding_CDS_not_defined, 4 retained_intron, 3 nonsense_mediated_decay

ENST00000219473, ENST00000540269, ENST00000562092, ENST00000562283, ENST00000562743, ENST00000563023, ENST00000563048, ENST00000563386, ENST00000563433, ENST00000563892, ENST00000564566, ENST00000566378, ENST00000566512, ENST00000567526, ENST00000569038, ENST00000569511, ENST00000569925, ENST00000570053, ENST00000570191, ENST00000853352, ENST00000853353, ENST00000853354, ENST00000853355, ENST00000933617, ENST00000933618, ENST00000933619, ENST00000933620, ENST00000933621, ENST00000933622, ENST00000933623, ENST00000933624, ENST00000933625, ENST00000933626, ENST00000946234

RefSeq mRNA: 2 — MANE Select: NM_005153 NM_001272075, NM_005153

CCDS: CCDS45537, CCDS62004

Canonical transcript exons

ENST00000219473 — 14 exons

Exon	Start	End
ENSE00002619793	84700000	84700111
ENSE00002628140	84778895	84779922
ENSE00003474509	84764086	84764263
ENSE00003485953	84760172	84760275
ENSE00003492787	84768193	84768358
ENSE00003507506	84775160	84775225
ENSE00003513274	84759891	84759946
ENSE00003520411	84759363	84759472
ENSE00003527943	84772541	84772685
ENSE00003548601	84733435	84733503
ENSE00003586956	84740309	84740369
ENSE00003632529	84762989	84763088
ENSE00003642164	84758716	84758807
ENSE00003649715	84744633	84745673

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 96.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.1717 / max 204.9543, expressed in 1818 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155336	28.2792	1817
155345	0.2989	49
155342	0.1608	61
207986	0.1473	58
155343	0.1470	51
155338	0.1150	48
155344	0.0184	8
155341	0.0051	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	96.71	gold quality
cortical plate	UBERON:0005343	96.31	gold quality
ganglionic eminence	UBERON:0004023	96.09	gold quality
secondary oocyte	CL:0000655	95.98	gold quality
embryo	UBERON:0000922	95.22	gold quality
blood	UBERON:0000178	94.87	gold quality
colonic epithelium	UBERON:0000397	94.63	gold quality
adrenal tissue	UBERON:0018303	94.40	gold quality
gastrocnemius	UBERON:0001388	94.24	gold quality
muscle of leg	UBERON:0001383	94.02	gold quality
monocyte	CL:0000576	93.90	gold quality
leukocyte	CL:0000738	93.89	gold quality
mononuclear cell	CL:0000842	93.82	gold quality
endometrium epithelium	UBERON:0004811	93.67	gold quality
sperm	CL:0000019	93.52	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.51	gold quality
stromal cell of endometrium	CL:0002255	93.23	gold quality
bone marrow cell	CL:0002092	92.60	gold quality
islet of Langerhans	UBERON:0000006	92.59	gold quality
bone marrow	UBERON:0002371	92.59	gold quality
sural nerve	UBERON:0015488	92.59	gold quality
granulocyte	CL:0000094	92.44	gold quality
male germ cell	CL:0000015	92.19	gold quality
rectum	UBERON:0001052	92.16	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.05	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.92	gold quality
lymph node	UBERON:0000029	91.89	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.82	gold quality
mucosa of stomach	UBERON:0001199	91.73	gold quality
skeletal muscle organ	UBERON:0014892	91.29	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

102 targeting USP10, 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-6833-3P	100.00	70.63	3197
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-1305	99.91	71.43	3443

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 59.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Ras-GAP SH3 domain binding protein (G3BP) is a modulator of USP10. G3BP does not appear to be a substrate of USP10; it rather inhibits its ability to disassemble ubiquitin chains. (PMID:11439350)
• The data indicate that USP10 is a new cofactor that binds to the androgen receptor (AR) and stimulates the androgen response of target promoters. This finding underlines the role of the ubiquitin/proteasome system in modulating the AR function. (PMID:16368182)
• RTQ-LDA and RTQ identified ubiquitin specific protease 10 as significantly over-expressed in dead-of-disease compared to long-term survival glioblastoma multiforme patients. (PMID:16773218)
• USP10 has a role in facilitating the deubiquitination of CFTR in early endosomes and thereby enhancing the endocytic recycling of CFTR (PMID:19398555)
• Findings reveal USP10 to be a novel regulator of p53, providing an alternative mechanism of p53 inhibition in cancers with wild-type p53. (PMID:20096447)
• a novel function for USP10 in facilitating the deubiquitination of CFTR in early endosomes, thereby enhancing the endocytic recycling and cell surface expression of CFTR. (PMID:20215869)
• USP10 mediates the deubiquitination of p53, regulating deubiquitination activity of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. (PMID:21962518)
• USP10 is a host factor that inhibits stress-induced reactive oxygen species production and apoptosis in HTLV-1-infected T cells. (PMID:23775713)
• USP10 inhibits genotoxic NF-kappaB activation by MCPIP1-facilitated deubiquitination of NEMO. (PMID:24270572)
• USP10 deubiquitinates and stabilizes SIRT6. (PMID:24332849)
• this study identified USP10, a carboxyl-terminal ubiquitin-processing protease, could interact with T-bet in the nucleus. (PMID:24845384)
• miR-191 could promote pancreatic cancer progression through targeting USP10, implicating a novel mechanism for the tumorigenesis. (PMID:25168367)
• Investigate the expression of USP10 in the human normal adrenal gland and various adrenal tumors. In adrenal tumors, detectable levels of USP10 protein were found in 100 % (30/30) adrenocortical adenomas, 88.89 % (8/9) adrenocortical carcinomas, and 10 % (2/20) pheochromocytomas. (PMID:26555087)
• Data demonstrated that AMPK-USP10 form a positive feedforward loop that ensures amplification of AMPK activation in response to fluctuation of cellular energy status. (PMID:26876938)
• G3BP mediates the condensation of stress granules by shifting between two different states that are controlled by the phosphorylation of S149 and by binding to Caprin1 or USP10. (PMID:27022092)
• Deubiquitylase USP10 interacts with RNF168 and TOP2alpha, and restrains ubiquitylation of TOP2alpha as well as its chromatin binding. (PMID:27558965)
• A controlling role for USP10 after wounding in determining myofibroblast development and activation of fibrotic TGFbeta signaling. (PMID:28851806)
• USP10 directly interacted with and stabilized PTEN via deubiquitination. (PMID:28852924)
• USP10 was expressed primarily in the cytoplasm of prostate cancer tissues. High levels of USP10 expression were strongly correlated with high levels of AR, G3BP2, and p53 in the cytoplasm. High expression of USP10 was significantly associated with poor prognosis of patients with prostate cancer. (PMID:29378906)
• USP10 inhibits hepatic steatosis, insulin resistance, and inflammation through Sirt6. (PMID:29698567)
• By using a genome wide siRNA screen for deubiquitinating enzymes, we identified USP10 as a deubiquitinase for Slug in cancer cells. USP10 interacts with Slug and mediates its degradation by the proteasome. Importantly, USP10 is concomitantly highly expressed with Slug in cancer biopsies. (PMID:29803676)
• Data show that ubiquitin-specific protease 10 (USP10) expression is downregulated and associated with poor prognosis inhepatocellular carcinoma (HCC). (PMID:30056112)
• One of the USP10 targets is TP53. Wildtype TP53 is usually rescued from proteasomal degradation by USP10. As most KMT2A leukemias display wildtype p53 alleles, one might argue that the disruption of an USP10 allele can be classified as a pro-oncogenic event. (PMID:30107050)
• USP10 silencing demonstrated the inverse effects, and these effects induced by USP10 silencing were significantly blocked by EGF. USP10 overexpression promoted Raf-1 protein expression, but not mRNA expression, through deubiquitination… these results suggest that USP10 promotes proliferation and migration and inhibits apoptosis of endometrial stromal cells in endometriosis through activating the Raf-1/MEK/ERK pathway (PMID:30281322)
• Loss of USP10 expression is associated with small intestinal adenocarcinoma. (PMID:30375264)
• Study determined that both USP10 and MSI2 proteins are upregulated in colon cancer cells. USP10 interacts with and regulate the expression of oncogenic factor Musashi-2 (MSI2) via deubiquitination of Lys-48 to regulate tumor proliferation. (PMID:30604502)
• RNAi Screening-based Identification of USP10 as a Novel Regulator of Paraptosis. (PMID:30894572)
• In keloid fibroblasts TRAF4 interacted with the deubiquitinase USP10 and blocked the access of p53 to USP10, resulting in p53 destabilization. Knockdown of p53 rescued cell proliferation in TRAF4-knockdown keloid fibroblasts, suggesting that the regulation of proliferation by TRAF4 in keloids relied on p53. In keloid patient samples, TRAF4 expression was inversely correlated with p53-p21 signaling activity. (PMID:30940456)
• USP10 functions as an NOTCH1 intracellular domain (NICD1) deubiquitinase that fine-tunes endothelial Notch responses during angiogenic sprouting. (PMID:30975888)
• USP10 is a critical factor for Tau-positive stress granule formation in neuronal cells. (PMID:31332267)
• G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10. (PMID:31501480)
• Decreased expression of USP10 or combined USP10/p14ARF decreased expression is a strong indicator of poor prognosis in patients with ovarian cancer. (PMID:31659108)
• Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein. (PMID:31721429)
• The deubiquitinase USP10 regulates KLF4 stability and suppresses lung tumorigenesis. (PMID:31748695)
• Potent USP10/13 antagonist spautin-1 suppresses melanoma growth via ROS-mediated DNA damage and exhibits synergy with cisplatin. (PMID:32129945)
• USP10 Promotes Proliferation of Hepatocellular Carcinoma by Deubiquitinating and Stabilizing YAP/TAZ. (PMID:32217697)
• The USP10-HDAC6 axis confers cisplatin resistance in non-small cell lung cancer lacking wild-type p53. (PMID:32382008)
• Ubiquitin-specific peptidase 7 (USP7) and USP10 mediate deubiquitination of human NHE3 regulating its expression and activity. (PMID:33095475)
• USP10 deletion inhibits macrophage-derived foam cell formation and cellular-oxidized low density lipoprotein uptake by promoting the degradation of CD36. (PMID:33197885)
• The ubiquitin isopeptidase USP10 deubiquitinates LC3B to increase LC3B levels and autophagic activity. (PMID:33577797)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp10	ENSDARG00000103422
mus_musculus	Usp10	ENSMUSG00000031826
rattus_norvegicus	Usp10	ENSRNOG00000016509

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), 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), USP15 (ENSG00000135655), 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 10 — Q14694 (reviewed: Q14694)

Alternative names: Deubiquitinating enzyme 10, Ubiquitin thioesterase 10, Ubiquitin-specific-processing protease 10

All UniProt accessions (11): Q14694, A0A7G6J4N4, H3BNA1, H3BNL0, H3BNP1, H3BNS8, H3BQC6, H3BQP1, H3BVF1, J3KT19, Q68D90

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolase that can remove conjugated ubiquitin from target proteins such as p53/TP53, RPS2/us5, RPS3/us3, RPS10/eS10, BECN1, SNX3 and CFTR. Acts as an essential regulator of p53/TP53 stability: in unstressed cells, specifically deubiquitinates p53/TP53 in the cytoplasm, leading to counteract MDM2 action and stabilize p53/TP53. Following DNA damage, translocates to the nucleus and deubiquitinates p53/TP53, leading to regulate the p53/TP53-dependent DNA damage response. Component of a regulatory loop that controls autophagy and p53/TP53 levels: mediates deubiquitination of BECN1, a key regulator of autophagy, leading to stabilize the PIK3C3/VPS34-containing complexes. In turn, PIK3C3/VPS34-containing complexes regulate USP10 stability, suggesting the existence of a regulatory system by which PIK3C3/VPS34-containing complexes regulate p53/TP53 protein levels via USP10 and USP13. Does not deubiquitinate MDM2. Plays a key role in 40S ribosome subunit recycling when a ribosome has stalled during translation: acts both by inhibiting formation of stress granules, which store stalled translation pre-initiation complexes, and mediating deubiquitination of 40S ribosome subunits. Acts as a negative regulator of stress granules formation by lowering G3BP1 and G3BP2 valence, thereby preventing G3BP1 and G3BP2 ability to undergo liquid-liquid phase separation (LLPS) and assembly of stress granules. Promotes 40S ribosome subunit recycling following ribosome dissociation in response to ribosome stalling by mediating deubiquitination of 40S ribosomal proteins RPS2/us5, RPS3/us3 and RPS10/eS10, thereby preventing their degradation by the proteasome. Part of a ribosome quality control that takes place when ribosomes have stalled during translation initiation (iRQC): USP10 acts by removing monoubiquitination of RPS2/us5 and RPS3/us3, promoting 40S ribosomal subunit recycling. Deubiquitinates CFTR in early endosomes, enhancing its endocytic recycling. Involved in a TANK-dependent negative feedback response to attenuate NF-kappa-B activation via deubiquitinating IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage. Deubiquitinates TBX21 leading to its stabilization. Plays a negative role in the RLR signaling pathway upon RNA virus infection by blocking the RIGI-mediated MAVS activation. Mechanistically, removes the unanchored ‘Lys-63’-linked polyubiquitin chains of MAVS to inhibit its aggregation, essential for its activation.

Subunit / interactions. Found in a deubiquitination complex with TANK, USP10 and ZC3H12A; this complex inhibits genotoxic stress- or interleukin-1-beta (IL1B)-mediated NF-kappa-B activation by promoting IKBKG or TRAF6 deubiquitination. Interacts with IKBKG; this interaction increases in response to DNA damage. Interacts with TANK; this interaction increases in response to DNA damage. Interacts with TRAF6; this interaction increases in response to DNA damage. Interacts with ZC3H12A; this interaction increases in response to DNA damage. Interacts with G3BP1 (via NTF2 domain) and G3BP2 (via NTF2 domain); inhibiting stress granule formation.

Subcellular location. Cytoplasm. Nucleus. Early endosome.

Tissue specificity. Widely expressed.

Post-translational modifications. Phosphorylated by ATM following DNA damage, leading to stabilization and translocation it to the nucleus. Ubiquitinated. Deubiquitinated by USP13.

Activity regulation. Specifically inhibited by spautin-1 (specific and potent autophagy inhibitor-1), a derivative of MBCQ that binds to USP10 and inhibits deubiquitinase activity. Regulated by PIK3C3/VPS34-containing complexes.

Induction. Following DNA damage. Down-regulated in renal cell carcinomas.

Similarity. Belongs to the peptidase C19 family. USP10 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q14694-1	1	yes
Q14694-2	2
Q14694-3	3

RefSeq proteins (2): NP_001259004, NP_005144* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR009818	PAM2_motif	Conserved_site
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050164	Peptidase_C19	Family

Pfam: PF00443, PF07145

UniProt features (51 total): modified residue 13, mutagenesis site 13, region of interest 6, compositionally biased region 5, sequence variant 3, active site 2, splice variant 2, sequence conflict 2, initiator methionine 1, chain 1, domain 1, strand 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8TH6	X-RAY DIFFRACTION	2.34
7XHF	X-RAY DIFFRACTION	2.68

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14694-F1	62.19	0.32

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): 424 (nucleophile); 749 (proton acceptor)

Post-translational modifications (13): 2, 24, 42, 100, 211, 226, 321, 337, 365, 370, 547, 563, 576

Mutagenesis-validated functional residues (13):

Position	Phenotype
10	abolished interaction with g3bp1 and ability to inhibit stress granule formation.
10	decreased but not abolished interaction with g3bp1.
11	decreased but not abolished interaction with g3bp1.
11	abolished interaction with g3bp1.
12	decreased but not abolished interaction with g3bp1.
12	abolished interaction with g3bp1.
13	abolished interaction with g3bp1.
13	decreased but not abolished interaction with g3bp1.
42	abolishes phosphorylation by atm; when associated with a-337.
42	phospho-mimetic mutant that translocates to the nucleus in absence of genotoxic stress; when associated with d-337.
337	abolishes phosphorylation by atm; when associated with a-42.
337	phospho-mimetic mutant that translocates to the nucleus in absence of genotoxic stress; when associated with e-42.
424	abolishes deubiquitinating activity and ability to deubiquitinate 40s ribosomal proteins.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5656169	Termination of translesion DNA synthesis
R-HSA-5689880	Ub-specific processing proteases

MSigDB gene sets: 234 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_DNA_DAMAGE_TOLERANCE, WONG_PROTEASOME_GENE_MODULE, CACCAGC_MIR138, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_NEGATIVE_REGULATION_OF_ORGANELLE_ASSEMBLY, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_TRANSLATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, WATANABE_RECTAL_CANCER_RADIOTHERAPY_RESPONSIVE_UP

GO Biological Process (19): DNA repair (GO:0006281), proteolysis (GO:0006508), autophagy (GO:0006914), DNA damage response (GO:0006974), regulation of autophagy (GO:0010506), protein deubiquitination (GO:0016579), translesion synthesis (GO:0019985), DNA damage response, signal transduction by p53 class mediator (GO:0030330), regulation of protein stability (GO:0031647), monoubiquitinated protein deubiquitination (GO:0035520), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), innate immune response (GO:0045087), negative regulation of stress granule assembly (GO:0062030), cellular response to interleukin-1 (GO:0071347), rescue of stalled cytosolic ribosome (GO:0072344), chromatin remodeling (GO:0006338), protein monoubiquitination (GO:0006513), stress granule assembly (GO:0034063), ribosome-associated ubiquitin-dependent protein catabolic process (GO:1990116)

GO Molecular Function (10): p53 binding (GO:0002039), RNA binding (GO:0003723), cysteine-type endopeptidase activity (GO:0004197), cysteine-type deubiquitinase activity (GO:0004843), transmembrane transporter binding (GO:0044325), molecular function inhibitor activity (GO:0140678), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (9): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), early endosome (GO:0005769), cytosol (GO:0005829), cytosolic ribosome (GO:0022626), protein-containing complex (GO:0032991), intermediate filament cytoskeleton (GO:0045111), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein binding	2
cysteine-type peptidase activity	2
DNA metabolic process	1
DNA damage response	1
protein metabolic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
cellular response to stress	1
autophagy	1
regulation of catabolic process	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
DNA damage tolerance	1
DNA synthesis involved in DNA replication	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
regulation of biological quality	1
protein deubiquitination	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
immune response	1
defense response to symbiont	1
stress granule assembly	1
regulation of stress granule assembly	1
negative regulation of organelle assembly	1
response to interleukin-1	1
cellular response to cytokine stimulus	1
cytoplasmic translational elongation	1
ribosome disassembly	1
chromatin organization	1
protein ubiquitination	1
membraneless organelle assembly	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
nucleic acid binding	1
endopeptidase activity	1
deubiquitinase activity	1
molecular function regulator activity	1

Protein interactions and networks

STRING

2182 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP10	G3BP1	Q13283	965
USP10	SH3BP5	O60239	926
USP10	USP1	O94782	669
USP10	USP13	Q92995	664
USP10	CAPRIN1	Q14444	639
USP10	G3BP2	Q9UN86	624
USP10	ZUP1	Q96AP4	531
USP10	ZC3H12A	Q5D1E8	500
USP10	TIA1	P31483	461
USP10	USP5	P45974	423
USP10	RBM42	Q9BTD8	421
USP10	USP7	Q93009	420
USP10	TIAL1	Q01085	418
USP10	USP25	Q9UHP3	413
USP10	YOD1	Q5VVQ6	402

IntAct

170 interactions, top by confidence:

A	B	Type	Score
G3BP1	N	psi-mi:“MI:0915”(physical association)	0.980
G3BP2	N	psi-mi:“MI:0915”(physical association)	0.970
G3BP1	USP10	psi-mi:“MI:0915”(physical association)	0.950
USP10	G3BP1	psi-mi:“MI:0915”(physical association)	0.950
G3BP2	USP10	psi-mi:“MI:0915”(physical association)	0.940
USP10	G3BP2	psi-mi:“MI:0915”(physical association)	0.940
G3BP1	CAPRIN1	psi-mi:“MI:0914”(association)	0.840
N	EIF2AK2	psi-mi:“MI:0914”(association)	0.820
YBX1	HNRNPR	psi-mi:“MI:0915”(physical association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RACK1	USP10	psi-mi:“MI:0915”(physical association)	0.670
CFTR	USP10	psi-mi:“MI:0915”(physical association)	0.660
USP10	CFTR	psi-mi:“MI:0915”(physical association)	0.660
USP10	ANKRD28	psi-mi:“MI:0914”(association)	0.610
USP10	G3BP2	psi-mi:“MI:0915”(physical association)	0.560
USP10		psi-mi:“MI:0915”(physical association)	0.560
USP10	GFAP	psi-mi:“MI:0915”(physical association)	0.560
USP10	JPH3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (636): G3BP2 (Two-hybrid), USP10 (Affinity Capture-MS), USP10 (Affinity Capture-MS), USP10 (Affinity Capture-MS), G3BP1 (Co-fractionation), SF3B3 (Co-fractionation), USP10 (Affinity Capture-MS), USP10 (Two-hybrid), USP10 (Affinity Capture-MS), USP10 (Affinity Capture-MS), USP10 (Affinity Capture-MS), USP10 (Affinity Capture-MS), USP10 (Affinity Capture-MS), USP10 (Affinity Capture-MS), USP10 (Affinity Capture-MS)

ESM2 similar proteins: A0JM59, A2BGT0, A5PJS6, A5PMR2, A5PN09, A6QNM7, A7Z056, B1AY15, B1WBD7, D2HBJ8, E1C213, E7F6T8, E9QG68, O88974, P52479, Q0V9G5, Q14694, Q15047, Q1RMU2, Q28CN3, Q2KJ09, Q2NL57, Q3KR59, Q5R5Z6, Q5RED8, Q5REG5, Q5XGZ2, Q5ZJN4, Q66H62, Q6NTR6, Q6P549, Q70CQ3, Q70CQ4, Q70EK9, Q7ZUM8, Q7ZXR7, Q80TQ2, Q8BW70, Q8C0R0, Q8C2S0

Diamond homologs: A0A0R4IB93, A1CIL1, A1CW53, A2Q9N1, A4FUN7, A5D9H7, A5PJS6, A5WWB0, A6QR55, B0Y4P5, B2GUZ1, B3LGK1, B8NSV5, C0HB46, D0RB01, E2RK09, E7F6T8, E9Q9U0, F1M625, F1N5V1, G5E8G2, G5E8I7, O22207, O24454, O57429, O60079, O75317, O94966, P34547, P35123, P35125, P38187, P39967, P40818, P50102, P51784, P52479, P62068, P62069, Q01988

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
USP10	“up-regulates quantity by stabilization”	TP53	deubiquitination
BECN1	“up-regulates quantity by stabilization”	USP10	deubiquitination
USP10	“up-regulates quantity by stabilization”	BECN1	deubiquitination
ATM	“up-regulates quantity by stabilization”	USP10	phosphorylation
PRKAA1	“up-regulates activity”	USP10	phosphorylation
ATM	“up-regulates activity”	USP10	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 132 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
Eukaryotic Translation Initiation	5	17.0×	3e-04
Cap-dependent Translation Initiation	5	17.0×	3e-04
SARS-CoV-1 modulates host translation machinery	5	17.0×	3e-04
Formation of the ternary complex, and subsequently, the 43S complex	7	16.6×	3e-05
Eukaryotic Translation Elongation	5	15.3×	4e-04
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	5	14.9×	4e-04
Translation initiation complex formation	7	14.6×	3e-05
Ribosomal scanning and start codon recognition	7	14.6×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of translation	11	18.1×	2e-08
translational initiation	6	18.1×	2e-04
cytoplasmic translation	11	17.1×	2e-08
positive regulation of translation	7	13.4×	2e-04
regulation of alternative mRNA splicing, via spliceosome	6	12.3×	1e-03
translation	12	10.4×	6e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	137
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3798 predictions. Top by Δscore:

Variant	Effect	Δscore
16:84700109:CAGGT:C	donor_loss	1.0000
16:84700110:AGGTA:A	donor_loss	1.0000
16:84700111:GGT:G	donor_loss	1.0000
16:84700112:G:C	donor_loss	1.0000
16:84700113:T:A	donor_loss	1.0000
16:84733431:TCAGT:T	acceptor_loss	1.0000
16:84733432:CA:C	acceptor_loss	1.0000
16:84733433:A:AG	acceptor_gain	1.0000
16:84733433:AG:A	acceptor_loss	1.0000
16:84733434:G:GG	acceptor_gain	1.0000
16:84733434:GT:G	acceptor_gain	1.0000
16:84733434:GTA:G	acceptor_gain	1.0000
16:84733434:GTAT:G	acceptor_gain	1.0000
16:84733434:GTATA:G	acceptor_gain	1.0000
16:84733500:TGAGG:T	donor_loss	1.0000
16:84733501:GAGG:G	donor_loss	1.0000
16:84733502:AGG:A	donor_loss	1.0000
16:84733504:GTAAG:G	donor_loss	1.0000
16:84733505:T:G	donor_loss	1.0000
16:84740305:GCA:G	acceptor_loss	1.0000
16:84740306:CA:C	acceptor_loss	1.0000
16:84740307:A:AC	acceptor_loss	1.0000
16:84740307:A:AG	acceptor_gain	1.0000
16:84740308:G:GG	acceptor_gain	1.0000
16:84740366:GATG:G	donor_gain	1.0000
16:84740367:ATGGT:A	donor_loss	1.0000
16:84740368:TGGTA:T	donor_loss	1.0000
16:84740370:GTA:G	donor_loss	1.0000
16:84740371:T:A	donor_loss	1.0000
16:84744630:CAGG:C	acceptor_loss	1.0000

AlphaMissense

5198 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:84758769:G:A	G416R	1.000
16:84758769:G:C	G416R	1.000
16:84758769:G:T	G416W	1.000
16:84758770:G:A	G416E	1.000
16:84758773:T:C	L417P	1.000
16:84758780:T:A	N419K	1.000
16:84758780:T:G	N419K	1.000
16:84758793:T:A	C424S	1.000
16:84758793:T:C	C424R	1.000
16:84758794:G:A	C424Y	1.000
16:84758794:G:C	C424S	1.000
16:84758794:G:T	C424F	1.000
16:84758795:C:G	C424W	1.000
16:84758796:T:G	Y425D	1.000
16:84758804:T:A	N427K	1.000
16:84758804:T:G	N427K	1.000
16:84759367:T:C	L430P	1.000
16:84759384:T:C	C436R	1.000
16:84759385:G:A	C436Y	1.000
16:84759386:C:G	C436W	1.000
16:84759403:T:C	L442P	1.000
16:84759910:T:C	F472L	1.000
16:84759911:T:C	F472S	1.000
16:84759912:C:A	F472L	1.000
16:84759912:C:G	F472L	1.000
16:84760223:C:A	P501H	1.000
16:84763001:G:C	D523H	1.000
16:84763002:A:C	D523A	1.000
16:84763002:A:G	D523G	1.000
16:84763002:A:T	D523V	1.000

dbSNP variants (sampled 300 via entrez): RS1000001568 (16:84779005 A>T), RS1000010798 (16:84735656 A>G), RS1000013148 (16:84709409 C>G,T), RS1000036949 (16:84708113 C>T), RS1000141000 (16:84712522 C>A,T), RS1000146446 (16:84703938 T>C), RS1000166414 (16:84756382 C>T), RS1000171030 (16:84739802 C>G,T), RS1000173009 (16:84723094 A>G), RS1000204209 (16:84778703 G>A), RS1000221707 (16:84712267 C>T), RS1000284088 (16:84724812 T>C), RS1000319422 (16:84707977 T>A,C), RS1000319820 (16:84777525 C>A,G), RS1000330802 (16:84737912 A>C)

Disease associations

OMIM: gene MIM:609818 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000175_24	Height	8.000000e-07
GCST002157_5	Response to mTOR inhibitor (everolimus)	6.000000e-06
GCST002938_14	Copper levels	2.000000e-06
GCST004611_209	High light scatter reticulocyte count	1.000000e-09
GCST004612_200	High light scatter reticulocyte percentage of red cells	5.000000e-10
GCST004619_171	Reticulocyte fraction of red cells	5.000000e-10
GCST004622_40	Reticulocyte count	2.000000e-09
GCST006417_6	Plasma factor VII activating protease levels	9.000000e-07
GCST90000025_102	Appendicular lean mass	4.000000e-13
GCST90002385_51	High light scatter reticulocyte count	3.000000e-10
GCST90002385_52	High light scatter reticulocyte count	3.000000e-14
GCST90002386_289	High light scatter reticulocyte percentage of red cells	8.000000e-10
GCST90002386_290	High light scatter reticulocyte percentage of red cells	4.000000e-15
GCST90002387_15	Immature fraction of reticulocytes	4.000000e-14
GCST90002405_314	Reticulocyte count	4.000000e-19
GCST90002406_439	Reticulocyte fraction of red cells	4.000000e-20

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005417	response to mTOR inhibitor
EFO:0007986	reticulocyte count
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3407323 (SINGLE PROTEIN)

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

ChEMBL bioactivities

16 potent at pChembl≥5 of 22 total, top 15 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.41	Kd	38.74	nM	CHEMBL5653589
7.41	ED50	38.74	nM	CHEMBL5653589
6.24	IC50	580	nM	CHEMBL2391504
6.22	IC50	600	nM	CHEMBL2391504
5.36	Kd	4331	nM	CHEMBL3752910
5.36	ED50	4331	nM	CHEMBL3752910
5.28	Kd	5240	nM	CHEMBL5549757
5.22	IC50	6000	nM	CHEMBL2159498
5.14	IC50	7200	nM	CHEMBL5549757
5.10	IC50	7900	nM	CHEMBL5558947
5.08	IC50	8400	nM	CHEMBL5512514
5.08	IC50	8300	nM	CHEMBL5559398
5.05	IC50	9000	nM	CHEMBL5523496
5.04	IC50	9200	nM	CHEMBL5527854
5.02	IC50	9500	nM	CHEMBL5558333

PubChem BioAssay actives

14 with measured affinity, of 60 total; 11 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149743: Binding affinity to human USP10 incubated for 45 mins by Kinobead based pull down assay	kd	0.0387	uM
6-fluoro-N-[(4-fluorophenyl)methyl]quinazolin-4-amine	2074082: Inhibition of USP10 (unknown origin)	ic50	0.5800	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149743: Binding affinity to human USP10 incubated for 45 mins by Kinobead based pull down assay	kd	4.3306	uM
N-[2-(4-chlorophenyl)ethyl]-2-[7-methyl-3-[3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl]-4-oxoquinolin-1-yl]acetamide	2064302: Binding affinity to GFP tagged human USP10 assessed as dissociation constant by Microscale thermophoresis analysis	kd	5.2400	uM
1-[5-(2,4-difluorophenyl)sulfanyl-4-nitrothiophen-2-yl]ethanone	2064337: Inhibition of USP10 (unknown origin) using K11-diubiquitin as substrate	ic50	6.0000	uM
N-[2-(4-chlorophenyl)ethyl]-2-[7-methoxy-3-[3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl]-4-oxoquinolin-1-yl]acetamide	2064299: Inhibition of human USP10 deubiquitinase activity using Ubiquitin 7-amino-4-carbamoylmethylcoumarin as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins by fluorometric assay	ic50	7.9000	uM
ethyl 5-(4-methoxycarbonylphenoxy)-4-nitrothiophene-2-carboxylate	2064339: Inhibition of human recombinant his tagged USP10 assessed as deubiquitinase activity	ic50	8.3000	uM
1-[2-[2-(4-chlorophenyl)ethylamino]-2-oxoethyl]-N-(2-methylphenyl)-7-morpholin-4-yl-4-oxoquinoline-3-carboxamide	2064299: Inhibition of human USP10 deubiquitinase activity using Ubiquitin 7-amino-4-carbamoylmethylcoumarin as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins by fluorometric assay	ic50	8.4000	uM
2-[3-(5-benzyl-1,3,4-oxadiazol-2-yl)-7-methyl-4-oxoquinolin-1-yl]-N-[2-(4-chlorophenyl)ethyl]acetamide	2064299: Inhibition of human USP10 deubiquitinase activity using Ubiquitin 7-amino-4-carbamoylmethylcoumarin as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins by fluorometric assay	ic50	9.0000	uM
N-[1-(4-chlorophenyl)piperidin-4-yl]-2-[7-methyl-3-[3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl]-4-oxoquinolin-1-yl]acetamide	2064299: Inhibition of human USP10 deubiquitinase activity using Ubiquitin 7-amino-4-carbamoylmethylcoumarin as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins by fluorometric assay	ic50	9.2000	uM
1-[2-[2-(4-chlorophenyl)ethylamino]-2-oxoethyl]-7-methyl-N-(2-methylphenyl)-4-oxo-1,8-naphthyridine-3-carboxamide	2064299: Inhibition of human USP10 deubiquitinase activity using Ubiquitin 7-amino-4-carbamoylmethylcoumarin as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins by fluorometric assay	ic50	9.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects binding, decreases reaction, decreases activity, decreases expression, affects cotreatment (+2 more)	3
bisphenol A	decreases expression, affects cotreatment	2
bisphenol S	affects cotreatment, increases methylation, decreases expression	2
Vehicle Emissions	decreases reaction, increases expression	2
Benzo(a)pyrene	decreases methylation, affects cotreatment, increases abundance, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Particulate Matter	decreases reaction, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
geldanamycin	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	increases expression	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation, increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
CPG-oligonucleotide	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
(+)-JQ1 compound	affects binding	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	decreases expression	1
Air Pollutants	increases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benztropine	affects cotreatment, increases expression	1
Caffeine	affects phosphorylation	1

ChEMBL screening assays

15 unique, capped per target: 15 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3412294	Binding	Inhibition of USP10 (unknown origin) by Ub-AMC assay	Inhibiting the deubiquitinating enzymes (DUBs). — J Med Chem

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 1 telomerase immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3KS	N/Tert-1 USP10	Telomerase immortalized cell line	Male
CVCL_D6CT	HyCyte THP-1 KO-hUSP10	Cancer cell line	Male
CVCL_D9VH	Ubigene HEK293 USP10 KO	Transformed cell line	Female
CVCL_TW48	HAP1 USP10 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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