USP4

Summary

USP4 (ubiquitin specific peptidase 4, HGNC:12627) is a protein-coding gene on chromosome 3p21.31, encoding Ubiquitin carboxyl-terminal hydrolase 4 (Q13107). Deubiquitinating enzyme that removes conjugated ubiquitin from target proteins.

The protein encoded by this gene is a protease that deubiquitinates target proteins such as ADORA2A and TRIM21. The encoded protein shuttles between the nucleus and cytoplasm and is involved in maintaining operational fidelity in the endoplasmic reticulum. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 7375 — RefSeq curated summary.

At a glance

• GWAS associations: 23
• Clinical variants (ClinVar): 151 total
• Druggable target: yes
• MANE Select transcript: NM_003363

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12627
Approved symbol	USP4
Name	ubiquitin specific peptidase 4
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	Unph
Ensembl gene	ENSG00000114316
Ensembl biotype	protein_coding
OMIM	603486
Entrez	7375

Gene structure

Transcript identifiers

Ensembl transcripts: 60 — 51 protein_coding, 7 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000265560, ENST00000351842, ENST00000415188, ENST00000416417, ENST00000431357, ENST00000461553, ENST00000462673, ENST00000464168, ENST00000475873, ENST00000483212, ENST00000485450, ENST00000486549, ENST00000488520, ENST00000491791, ENST00000877472, ENST00000877473, ENST00000877474, ENST00000877475, ENST00000877476, ENST00000877477, ENST00000877478, ENST00000877479, ENST00000877480, ENST00000877481, ENST00000877482, ENST00000877483, ENST00000877484, ENST00000877485, ENST00000877486, ENST00000877487, ENST00000877488, ENST00000877489, ENST00000877490, ENST00000877491, ENST00000877492, ENST00000877493, ENST00000911610, ENST00000911611, ENST00000911612, ENST00000965323, ENST00000965324, ENST00000965325, ENST00000965326, ENST00000965327, ENST00000965328, ENST00000965329, ENST00000965330, ENST00000965331, ENST00000965332, ENST00000965333, ENST00000965334, ENST00000965335, ENST00000965336, ENST00000965337, ENST00000965338, ENST00000965339, ENST00000965340, ENST00000965341, ENST00000965342, ENST00000965343

RefSeq mRNA: 3 — MANE Select: NM_003363 NM_001251877, NM_003363, NM_199443

CCDS: CCDS2793, CCDS2794, CCDS58832

Canonical transcript exons

ENST00000265560 — 22 exons

Exon	Start	End
ENSE00000768192	49324702	49324763
ENSE00000861562	49339924	49340053
ENSE00001912724	49277144	49278451
ENSE00003488912	49311514	49311654
ENSE00003504323	49302384	49302542
ENSE00003520445	49324894	49325039
ENSE00003539707	49278814	49278902
ENSE00003541573	49335469	49335596
ENSE00003550406	49297870	49297964
ENSE00003556043	49298552	49298635
ENSE00003557908	49283987	49284136
ENSE00003573208	49284466	49284584
ENSE00003573564	49284849	49284919
ENSE00003580600	49310620	49310737
ENSE00003585854	49286098	49286325
ENSE00003594701	49327686	49327816
ENSE00003636925	49292510	49292598
ENSE00003641325	49305715	49305888
ENSE00003654970	49300467	49300691
ENSE00003657276	49294407	49294598
ENSE00003672001	49325719	49325845
ENSE00003690669	49280744	49280847

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 98.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.6300 / max 409.2652, expressed in 1804 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42237	15.6709	1801
42238	0.7497	441
42236	0.2094	78

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	98.91	gold quality
cervix squamous epithelium	UBERON:0006922	98.01	gold quality
endothelial cell	CL:0000115	97.49	gold quality
sural nerve	UBERON:0015488	97.32	gold quality
blood	UBERON:0000178	96.68	gold quality
colonic epithelium	UBERON:0000397	96.49	gold quality
monocyte	CL:0000576	96.17	gold quality
mononuclear cell	CL:0000842	96.02	gold quality
leukocyte	CL:0000738	95.94	gold quality
tonsil	UBERON:0002372	95.50	gold quality
nipple	UBERON:0002030	95.32	gold quality
sperm	CL:0000019	95.15	gold quality
pylorus	UBERON:0001166	95.04	gold quality
visceral pleura	UBERON:0002401	94.99	gold quality
granulocyte	CL:0000094	94.95	gold quality
male germ cell	CL:0000015	94.76	gold quality
inferior olivary complex	UBERON:0002127	94.40	gold quality
lateral globus pallidus	UBERON:0002476	94.24	gold quality
bone marrow cell	CL:0002092	94.14	gold quality
parotid gland	UBERON:0001831	94.13	gold quality
lower esophagus mucosa	UBERON:0035834	93.94	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.93	gold quality
pleura	UBERON:0000977	93.77	gold quality
bone marrow	UBERON:0002371	93.73	gold quality
upper lobe of left lung	UBERON:0008952	93.67	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.58	gold quality
spleen	UBERON:0002106	93.56	gold quality
amniotic fluid	UBERON:0000173	93.55	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.52	gold quality
lymph node	UBERON:0000029	93.45	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	166.45
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

63 targeting USP4, 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-513A-5P	100.00	69.77	2465
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-6877-3P	98.98	65.83	560
HSA-MIR-4326	98.97	67.63	962

Literature-anchored findings (GeneRIF, showing 40)

• These results suggest that UnpEL colocalizes with the unubiquitinated form of Ro52 to the cytoplasmic rod-like structures. (PMID:16316627)
• Ro52 and UnpEL transregulate each other by ubiquitination and deubiquitination (PMID:16472766)
• modulation of USP4 expression may provide a new means to interfere with canonical Wnt signalling in a variety of physiological and pathological conditions (PMID:20141612)
• Results demonstrate that USP4 serves as a critical control to downregulate TNFalpha-induced NF-kappaB activation through deubiquitinating TAK1. (PMID:21331078)
• Studies indicate that the cylindromatosis/turban tumor syndrome gene (CYLD) ranked highest, followed by acylaminoacyl-peptidase (APEH), dystroglycan (DAG1), macrophage-stimulating protein (MST1) and ubiquitin-specific peptidase 4 (USP4). (PMID:21931648)
• USP4 deubiquitinates both TRAF2 and TRAF6 in vivo and in vitro in a deubiquitinase activity-dependent manner and inhibits TNFalpha-induced cancer cell migration. (PMID:22029577)
• USP4 plays an essential role in negative regulation of the TLR/IL-1R signaling-mediated innate immune response (PMID:22262844)
• identify the Ubiquitin-Specific Protease 4 (USP4) as an enzyme that removes ubiquitin from PDK1 in vivo and in vitro and co-localizes with PDK1 at the plasma membrane when the two proteins are overexpressed, indicating direct deubiquitination (PMID:22347420)
• Results uncover USP4 as an important determinant for crosstalk between TGF-beta/TGF-beta type I receptor and AKT signalling pathways. (PMID:22706160)
• the interaction with USP4 may regulate the structure and function of the proteasome or the turnover of specific proteasomal substrates. (PMID:23022198)
• Data suggest that USP4 down-regulates RIP1 (receptor-interacting serine-threonine kinase 1)-mediated TNFalpha (tumor necrosis factor-alpha) activation and promotes TNFalpha-induced apoptosis via deubiquitination of RIP1 in head/neck carcinoma. (PMID:23313255)
• Authors identified USP4 as a new positive regulator for RIG-I that acts through deubiquitinating K48-linked ubiquitin chains and stabilizing RIG-I. (PMID:23388719)
• USP4 overexpression is associated with hepatocellular carcinoma. (PMID:24798342)
• USP4 requires its N-terminal DUSP-Ubl domain to achieve full catalytic turnover by promoting ubiquitin exchange. (PMID:25404403)
• USP4 and IL-17 mRNA, but not RORgammat mRNA, were significantly elevated in CD4(+) T cells from patients with rheumatic heart disease (PMID:25821221)
• USP4 knockdown in HCT116, a colon cancer cell line, reduced invasion and migration activity. (PMID:26189775)
• USP4 cooperates with CtIP in DNA double-strand break end resection. (PMID:26387952)
• USP4 inhibits p53 and NF-kappaB through deubiquitinating and stabilizing HDAC2 (PMID:26411366)
• findings thus identify USP4 as a novel DNA repair regulator and invoke a model in which ubiquitin adducts regulate USP enzyme interactions and functions. (PMID:26455393)
• Results demonstrate that aberrant expression of USP4 contributes to the development and progression of colorectal cancer and reveal a critical mechanism underlying USP4-mediated oncogenic activity. (PMID:26669864)
• Ubiquitin-specific protease 4 (USP4), recently identified as a beta-catenin-specific deubiquitinylating enzyme, was highly expressed in PC14PE6/LvBr4 cells and involved in the increased stability of beta-catenin protein. (PMID:26883469)
• These results identify USP4 as a novel regulator of Dvl in Wnt/beta-catenin signal and show its involvement in Wnt3a-induced osteoblast differentiation (PMID:27128386)
• ubiquitin-specific protease 4 (USP4) is a binding partner of RNPS1. (PMID:27990632)
• Data suggest that ubiquitin specific protease 4 (USP4) interacts with interferon regulatory factor 8 (IRF8) and, by its Lys48-specific deubiquitinase/endopeptidase activity, stabilizes IRF8 protein levels in regulatory T-lymphocytes; USP4 and IRF8 are also expressed in helper T-lymphocytes. (PMID:28477415)
• The data indicate that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be related to the pathological process of rheumatic heart disease. (PMID:28791349)
• Data showed significantly increased expression of USP4 in cancer tissues compared to that in para-carcinoma tissues. (PMID:28946564)
• cyclophilin A (CypA) was identified as an important molecule for USP4-mediated oncogenic activity in hepatocellular carcinoma. (PMID:29396555)
• the up-regulated USP4 plays an oncogenic role in melanoma by simultaneously suppressing stress-induced cell apoptosis and facilitating tumour metastasis. (PMID:29542252)
• functions as a pivotal suppressor in nonalcoholic fatty liver disease (PMID:29573006)
• USP4 expression was significantly down-regulated in lung adenocarcinoma. USP4 expression might be a favorable biomarker in terms of overall survival and recurrence-free survival in the lung adenocarcinoma patients. (PMID:29667299)
• Study provide a novel mechanistic insight into the growth-regulatory role of TRPS1-USP4-HDAC2 axis by providing evidence that TRPS1 recruits USP4 to deubiquitinate and stabilize HDAC2. This is the first example of the non-transcription factor function of GATA transcription factor which affects the ubiquitination and transcription repressive function of HDAC2, acetylation of H4K16, and the deubiquitinase function of USP4. (PMID:30071870)
• We show here that mutating the active site cysteine of human USP4 and yeast Ubp8 to alanine increases the affinity of the DUB for mono- or diubiquitin by 10-150-fold. (PMID:30150323)
• USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-beta signaling-induced epithelial-mesenchymal transition, promoting hepatocellular carcinoma metastasis. (PMID:30335615)
• a novel H19/miR-148a/USP4 axis which promoted liver fibrosis via TGF-beta pathway in both hepatic stellate cells and hepatocytes, is reported. (PMID:30362572)
• modifications of USP15 and USP4 by phosphorylation are important for the regulation of their localization required for cellular function in the spliceosome. (PMID:31330151)
• The Effects of the Transforming Growth Factor-beta1 (TGF-beta1) Signaling Pathway on Cell Proliferation and Cell Migration are Mediated by Ubiquitin Specific Protease 4 (USP4) in Hypertrophic Scar Tissue and Primary Fibroblast Cultures. (PMID:32308208)
• Ubiquitin-specific protease 4 predicts an unfavorable prognosis and promotes malignant behaviors in vitro in pancreatic cancer. (PMID:33038351)
• Deubiquitinating enzymes USP4 and USP17 finetune the trafficking of PDGFRbeta and affect PDGF-BB-induced STAT3 signalling. (PMID:35064336)
• Transcriptome Analysis and Single-Cell Sequencing Analysis Constructed the Ubiquitination-Related Signature in Glioma and Identified USP4 as a Novel Biomarker. (PMID:35774799)
• The Deubiquitinating Enzyme USP4 Functions as an Oncoprotein in Gastric Cancer and Mediates NF-kappaB Signaling by Regulating PRL-3 Expression. (PMID:36336860)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000100224
mus_musculus	Usp4	ENSMUSG00000032612
rattus_norvegicus	Usp4	ENSRNOG00000054863

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), 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 4 — Q13107 (reviewed: Q13107)

Alternative names: Deubiquitinating enzyme 4, Ubiquitin thioesterase 4, Ubiquitin-specific-processing protease 4, Ubiquitous nuclear protein homolog

All UniProt accessions (3): Q13107, C9JNU9, H7C189

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinating enzyme that removes conjugated ubiquitin from target proteins. Deubiquitinates PDPK1. Deubiquitinates TRIM21. Deubiquitinates receptor ADORA2A which increases the amount of functional receptor at the cell surface. Deubiquitinates HAS2. Deubiquitinates MAVs leading to maintain MAVS protein stability, resulting in increased production of type I interferons (IFN-I) and enhanced antiviral innate immune responses against viral infections. Deubiquitinates RHEB in response to EGF signaling, promoting mTORC1 signaling. May regulate mRNA splicing through deubiquitination of the U4 spliceosomal protein PRPF3. This may prevent its recognition by the U5 component PRPF8 thereby destabilizing interactions within the U4/U6.U5 snRNP. May also play a role in the regulation of quality control in the ER.

Subunit / interactions. Interacts with RB1 (both dephosphorylated and hypophosphorylated forms). Interacts with RBL1 and RBL2. Interacts with ADORA2A (via cytoplasmic C-terminus); the interaction is direct. Interacts with SART3; recruits USP4 to its substrate PRPF3.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Overexpressed in small cell tumors and adenocarcinomas of the lung compared to wild-type lung (at protein level). Expressed in the hippocampal neurons.

Post-translational modifications. Phosphorylated at Ser-445 by PKB/AKT1 in response to EGF stimulus, promoting its ability deubiquitinate RHEB. Monoubiquitinated by TRIM21. Ubiquitination does not lead to its proteasomal degradation. Autodeubiquitinated.

Activity regulation. The completion of the deubiquitinase reaction is mediated by the DUSP and ubiquitin-like 1 domains which promotes the release of ubiquitin from the catalytic site enabling subsequent reactions to occur.

Domain organisation. The DUSP and ubiquitin-like 1 domains promote ubiquitin release and thus enhance USB4 catalytic activity. However, these domains do not bind ubiquitin.

Similarity. Belongs to the peptidase C19 family. USP4 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13107-1	1, UnpEL	yes
Q13107-2	2, UnpES
Q13107-3	3

RefSeq proteins (3): NP_001238806, NP_003354, NP_955475 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR006615	Pept_C19_DUSP	Domain
IPR018200	USP_CS	Conserved_site
IPR028135	Ub_USP-typ	Domain
IPR028889	USP	Domain
IPR035927	DUSP-like_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050185	Ub_carboxyl-term_hydrolase	Family

Pfam: PF00443, PF06337, PF14836

UniProt features (114 total): strand 31, helix 19, mutagenesis site 18, region of interest 10, turn 7, compositionally biased region 6, domain 4, binding site 4, modified residue 4, splice variant 3, short sequence motif 2, active site 2, sequence conflict 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2Y6E	X-RAY DIFFRACTION	2.4
5CTR	X-RAY DIFFRACTION	3.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13107-F1	77.03	0.36

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): 311 (nucleophile); 881 (proton acceptor)

Ligand- & substrate-binding residues (4): 461; 464; 799; 802

Post-translational modifications (4): 445, 655, 675, 680

Mutagenesis-validated functional residues (18):

Position	Phenotype
24	moderate reduction in thiol-dependent deubiquitinase activity.
40	moderate reduction in thiol-dependent deubiquitinase activity.
51	moderate reduction in thiol-dependent deubiquitinase activity.
88	severe reduction in thiol-dependent deubiquitinase activity.
88	moderate reduction in thiol-dependent deubiquitinase activity.
89	severe reduction in thiol-dependent deubiquitinase activity.
90	moderate reduction in thiol-dependent deubiquitinase activity.
91	moderate reduction in thiol-dependent deubiquitinase activity.
92	severe reduction in thiol-dependent deubiquitinase activity.
134	severe reduction in thiol-dependent deubiquitinase activity.
136	severe reduction in thiol-dependent deubiquitinase activity.
311	loss of thiol-dependent deubiquitinase activity. its ubiquitination by trim21 is enhanced. does affect interaction with
384–385	severe reduction in thiol-dependent deubiquitinase activity.
386	lowers affinity for ubiquitin characterized by a 10-fold increase in ubiquitin release and a slight reduction in ubiquit
445	abolished phosphorylation by pkb/akt1 in response to egf signaling.
445	mimics phosphorylation; promoting association with rheb.
459–463	reduces the interaction with rb1.
463	reduces the interaction with rb1.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5357786	TNFR1-induced proapoptotic signaling
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-5357956	TNFR1-induced NF-kappa-B signaling pathway
R-HSA-5689880	Ub-specific processing proteases

MSigDB gene sets: 172 (showing top): RNGTGGGC_UNKNOWN, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, WONG_PROTEASOME_GENE_MODULE, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_2NM_UP, GOBP_SPLICEOSOMAL_TRI_SNRNP_COMPLEX_ASSEMBLY, WATANABE_RECTAL_CANCER_RADIOTHERAPY_RESPONSIVE_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, GOBP_RNA_SPLICING, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (14): spliceosomal tri-snRNP complex assembly (GO:0000244), proteolysis (GO:0006508), protein deubiquitination (GO:0016579), negative regulation of protein ubiquitination (GO:0031397), regulation of protein stability (GO:0031647), protein localization to cell surface (GO:0034394), positive regulation of TORC1 signaling (GO:1904263), cytoplasmic translation (GO:0002181), cellular response to starvation (GO:0009267), cellular response to nutrient levels (GO:0031669), TORC1 signaling (GO:0038202), negative regulation of translational initiation (GO:0045947), positive regulation of translational initiation (GO:0045948), negative regulation of TORC1 signaling (GO:1904262)

GO Molecular Function (9): cysteine-type deubiquitinase activity (GO:0004843), adenosine receptor binding (GO:0031685), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), deubiquitinase activity (GO:0101005)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), lysosome (GO:0005764), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TNF signaling	3
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
TORC1 signaling	2
regulation of TORC1 signaling	2
translational initiation	2
regulation of translational initiation	2
cellular anatomical structure	2
spliceosomal snRNP assembly	1
protein metabolic process	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
regulation of biological quality	1
intracellular protein localization	1
positive regulation of TOR signaling	1
translation	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
response to nutrient levels	1
cellular response to stimulus	1
TOR signaling	1
negative regulation of translation	1
positive regulation of translation	1
negative regulation of TOR signaling	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
G protein-coupled receptor binding	1
protein binding	1
cation binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
ubiquitin-like protein peptidase activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
lytic vacuole	1
cytoplasm	1

Protein interactions and networks

STRING

2242 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP4	SART3	Q15020	935
USP4	RBBP8	Q99708	897
USP4	TGFBR1	P36897	860
USP4	TRIM21	P19474	846
USP4	ZUP1	Q96AP4	735
USP4	TRAF6	Q9Y4K3	660
USP4	CYLD	Q9NQC7	658
USP4	PRPF3	O43395	653
USP4	USP25	Q9UHP3	624
USP4	OTUB1	Q96FW1	607
USP4	MYSM1	Q5VVJ2	606
USP4	TP53	P04637	605
USP4	UCHL5	Q9Y5K5	604
USP4	USP5	P45974	603
USP4	USP28	Q96RU2	592

IntAct

72 interactions, top by confidence:

A	B	Type	Score
PSMC5	PSMD11	psi-mi:“MI:0914”(association)	0.730
MAP3K6	YWHAG	psi-mi:“MI:0914”(association)	0.640
USP4	PRPF3	psi-mi:“MI:0914”(association)	0.640
ADORA2A	USP4	psi-mi:“MI:0915”(physical association)	0.590
USP4	ADORA2A	psi-mi:“MI:0915”(physical association)	0.590
ADORA2A	USP4	psi-mi:“MI:0407”(direct interaction)	0.590
USP4	USP4	psi-mi:“MI:0407”(direct interaction)	0.560
HES6	TLE1	psi-mi:“MI:0914”(association)	0.550
USP4	PRPF4	psi-mi:“MI:0914”(association)	0.530
CT55	BLTP3B	psi-mi:“MI:0914”(association)	0.530
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
STN1	SMCO3	psi-mi:“MI:0914”(association)	0.530
RNF19B	PIK3R2	psi-mi:“MI:0914”(association)	0.530
TCEAL1	CHEK1	psi-mi:“MI:0914”(association)	0.530
SLX1A	BACH1	psi-mi:“MI:0914”(association)	0.530
INSYN2A	CHUK	psi-mi:“MI:0914”(association)	0.530
RAB30	UBB	psi-mi:“MI:0914”(association)	0.530
ELMO1	CALML3	psi-mi:“MI:0914”(association)	0.530
LRRC27	HMOX1	psi-mi:“MI:0914”(association)	0.530
USP4	CTC1	psi-mi:“MI:0914”(association)	0.530
USP15	PRPF3	psi-mi:“MI:0914”(association)	0.530
USP4	RIPK1	psi-mi:“MI:0915”(physical association)	0.520
RIPK1	USP4	psi-mi:“MI:0915”(physical association)	0.520
USP4	RPL6	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (444): PLA2G2A (Biochemical Activity), UBC (Biochemical Activity), USP4 (Affinity Capture-Western), PCNA (Biochemical Activity), UBC (Reconstituted Complex), USP4 (Affinity Capture-MS), USP4 (Affinity Capture-MS), USP4 (Affinity Capture-MS), USP4 (Affinity Capture-MS), USP4 (Affinity Capture-MS), TCF7L2 (Reconstituted Complex), TCF7L2 (Affinity Capture-Western), RORC (Affinity Capture-Western), HDAC2 (Affinity Capture-Western), USP4 (Affinity Capture-Western)

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

4 interactions.

A	Effect	B	Mechanism
USP4	“down-regulates activity”	PRPF3	deubiquitination
USP4	“up-regulates quantity by stabilization”	BRAP	deubiquitination
AKT1	“up-regulates quantity by stabilization”	USP4	phosphorylation
DNPEP	“down-regulates quantity by destabilization”	USP4	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 88 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
ER-Phagosome pathway	5	11.4×	9e-03
Downstream TCR signaling	5	11.3×	9e-03
KEAP1-NFE2L2 pathway	5	10.5×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	113
Likely benign	9
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3940 predictions. Top by Δscore:

Variant	Effect	Δscore
3:49278448:TAGT:T	acceptor_gain	1.0000
3:49278450:GT:G	acceptor_gain	1.0000
3:49278451:TCTGA:T	acceptor_loss	1.0000
3:49278452:C:CC	acceptor_gain	1.0000
3:49280742:A:AC	donor_gain	1.0000
3:49280743:C:CC	donor_gain	1.0000
3:49280743:CA:C	donor_gain	1.0000
3:49280843:GCCCT:G	acceptor_gain	1.0000
3:49280844:CCCT:C	acceptor_gain	1.0000
3:49280844:CCCTC:C	acceptor_gain	1.0000
3:49280845:CCTC:C	acceptor_gain	1.0000
3:49280846:CT:C	acceptor_gain	1.0000
3:49280848:C:CC	acceptor_gain	1.0000
3:49280853:C:CT	acceptor_gain	1.0000
3:49280855:C:CT	acceptor_gain	1.0000
3:49280856:A:T	acceptor_gain	1.0000
3:49284019:ATC:A	donor_gain	1.0000
3:49284460:GCGTA:G	donor_loss	1.0000
3:49284461:CGTA:C	donor_loss	1.0000
3:49284462:GTA:G	donor_loss	1.0000
3:49284463:TA:T	donor_loss	1.0000
3:49284464:A:AC	donor_gain	1.0000
3:49284465:C:CC	donor_gain	1.0000
3:49284465:C:CT	donor_loss	1.0000
3:49284479:C:CA	donor_gain	1.0000
3:49284480:C:A	donor_gain	1.0000
3:49284583:GCCT:G	acceptor_loss	1.0000
3:49284585:C:CC	acceptor_gain	1.0000
3:49284585:C:CG	acceptor_loss	1.0000
3:49284586:T:G	acceptor_loss	1.0000

AlphaMissense

6368 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:49278427:A:C	Y920D	1.000
3:49278432:A:G	L918P	1.000
3:49278851:T:A	D899V	1.000
3:49278851:T:G	D899A	1.000
3:49278852:C:G	D899H	1.000
3:49278867:A:G	W894R	1.000
3:49278867:A:T	W894R	1.000
3:49280744:A:G	Y882H	1.000
3:49280745:G:C	H881Q	1.000
3:49280745:G:T	H881Q	1.000
3:49280747:G:C	H881D	1.000
3:49280749:C:A	G880V	1.000
3:49280749:C:T	G880D	1.000
3:49280750:C:G	G880R	1.000
3:49280764:C:T	G875E	1.000
3:49280769:A:C	H873Q	1.000
3:49280769:A:T	H873Q	1.000
3:49280771:G:C	H873D	1.000
3:49284016:C:A	K837N	1.000
3:49284016:C:G	K837N	1.000
3:49284022:C:A	R835S	1.000
3:49284022:C:G	R835S	1.000
3:49284023:C:G	R835T	1.000
3:49284043:G:C	F828L	1.000
3:49284043:G:T	F828L	1.000
3:49284044:A:C	F828C	1.000
3:49284044:A:G	F828S	1.000
3:49284045:A:G	F828L	1.000
3:49284048:G:T	R827S	1.000
3:49284049:T:A	K826N	1.000

dbSNP variants (sampled 300 via entrez): RS1000096292 (3:49339760 C>G), RS1000274103 (3:49316636 T>A), RS1000346645 (3:49336555 G>A), RS1000375290 (3:49328776 C>A,T), RS1000402604 (3:49309488 C>A,T), RS1000473821 (3:49321768 C>T), RS1000525039 (3:49306809 A>G), RS1000557358 (3:49313035 C>T), RS1000583676 (3:49317020 T>C), RS1000616534 (3:49322076 C>T), RS1000732717 (3:49280433 C>T), RS1000805642 (3:49282313 C>T), RS1000817205 (3:49281127 CCCGA>C), RS1000852268 (3:49334476 G>A), RS1000863060 (3:49286937 C>T)

Disease associations

OMIM: gene MIM:603486 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST001725_77	Inflammatory bowel disease	1.000000e-47
GCST002548_9	Ulcerative colitis	8.000000e-07
GCST004131_23	Inflammatory bowel disease	1.000000e-33
GCST004132_17	Crohn’s disease	3.000000e-23
GCST004133_11	Ulcerative colitis	8.000000e-20
GCST004612_58	High light scatter reticulocyte percentage of red cells	6.000000e-46
GCST004619_7	Reticulocyte fraction of red cells	2.000000e-49
GCST004622_159	Reticulocyte count	3.000000e-46
GCST005316_397	Intelligence (MTAG)	6.000000e-11
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST007954_9	Glycated hemoglobin levels	8.000000e-10
GCST009524_119	Household income (MTAG)	3.000000e-08
GCST010002_422	Refractive error	4.000000e-14
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13
GCST90002388_194	Lymphocyte count	3.000000e-12
GCST90002390_480	Mean corpuscular hemoglobin	5.000000e-17
GCST90002392_189	Mean corpuscular volume	9.000000e-17
GCST90002404_45	Red cell distribution width	3.000000e-19
GCST90002406_30	Reticulocyte fraction of red cells	2.000000e-28

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0004337	intelligence
EFO:0004541	HbA1c measurement
EFO:0009695	household income
EFO:0004346	neuroimaging measurement
EFO:0004587	lymphocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2406900 (SINGLE PROTEIN)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.30	IC50	50	nM	CHEMBL4593739
5.82	IC50	1500	nM	VIALININ A
5.41	EC50	3900	nM	CHEMBL4303622

PubChem BioAssay actives

3 with measured affinity, of 14 total; 3 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-(2-chloroacetyl)-N-[(4-ethynylphenyl)methyl]-1-methylpyrrole-2-carboxamide	1558724: Inhibition of USP4 in human U2OS using Ub-TAMRA substrate by Ub-Rhodamine fluorescent intensity assay	ic50	0.0500	uM
[3,4-dihydroxy-2,5-bis(4-hydroxyphenyl)-6-(2-phenylacetyl)oxyphenyl] 2-phenylacetate	761508: Inhibition of human USP4 using Ub-AMC as substrate after 60 mins by fluorometric analysis	ic50	1.5000	uM
(2,6-diamino-5-thiocyanato-3-pyridinyl) thiocyanate	1925872: Inhibition of USP4 (unknown origin)	ec50	3.9000	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
torcetrapib	increases expression	2
Resveratrol	affects cotreatment, increases expression	2
Valproic Acid	affects expression, decreases expression	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Caffeine	increases phosphorylation	1
Coumestrol	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Ellagic Acid	decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	increases expression, affects cotreatment	1
Quercetin	decreases expression	1
Selenium	decreases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Vitamin E	decreases expression	1
Cyclosporine	increases expression	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	decreases methylation	1

ChEMBL screening assays

13 unique, capped per target: 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2411914	Binding	Binding affinity to human USP4 after 1 hr by SDS-PAGE analysis	Vialinin A is a ubiquitin-specific peptidase 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_TW96	HAP1 USP4 (-) 1	Cancer cell line	Male
CVCL_XU94	HAP1 USP4 (-) 2	Cancer cell line	Male
CVCL_XU95	HAP1 USP4 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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