USP22

Summary

USP22 (ubiquitin specific peptidase 22, HGNC:12621) is a protein-coding gene on chromosome 17p11.2, encoding Ubiquitin carboxyl-terminal hydrolase 22 (Q9UPT9). Deubiquitinase that plays a role in several cellular processes including transcriptional regulation, cell cycle progression or innate immunity.

Enables deubiquitinase activity; enzyme binding activity; and transcription coactivator activity. Contributes to histone H4 acetyltransferase activity. Involved in several processes, including G2/M transition of mitotic cell cycle; protein deubiquitination; and regulation of gene expression. Part of SAGA complex.

Source: NCBI Gene 23326 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 51 total
• Druggable target: yes
• MANE Select transcript: NM_015276

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12621
Approved symbol	USP22
Name	ubiquitin specific peptidase 22
Location	17p11.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1063
Ensembl gene	ENSG00000124422
Ensembl biotype	protein_coding
OMIM	612116
Entrez	23326

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 11 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000261497, ENST00000455117, ENST00000463692, ENST00000476111, ENST00000478443, ENST00000537526, ENST00000577610, ENST00000578446, ENST00000579645, ENST00000582335, ENST00000584538, ENST00000884362, ENST00000929028, ENST00000929029, ENST00000929030, ENST00000929031, ENST00000952978

RefSeq mRNA: 1 — MANE Select: NM_015276 NM_015276

CCDS: CCDS42285

Canonical transcript exons

ENST00000261497 — 13 exons

Exon	Start	End
ENSE00001262191	21042665	21043011
ENSE00003472614	21021113	21021226
ENSE00003499196	21007870	21007996
ENSE00003509068	21006896	21006987
ENSE00003510260	21019084	21019185
ENSE00003533327	21015752	21015899
ENSE00003583108	21012830	21012935
ENSE00003597206	21028542	21028674
ENSE00003599368	21011151	21011309
ENSE00003620756	21004928	21004990
ENSE00003684048	21004202	21004351
ENSE00003718132	20999596	21003073
ENSE00003791490	21017942	21018111

Expression profiles

Bgee: expression breadth ubiquitous, 304 present calls, max score 99.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 118.6986 / max 545.5590, expressed in 1825 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164916	93.4807	1825
164917	10.7090	1767
164918	6.7281	1691
164915	3.1001	1482
164906	2.6311	1252
164919	0.5934	325
164909	0.5271	211
208093	0.3894	192
164914	0.2731	106
164920	0.2666	110

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
paraflocculus	UBERON:0005351	99.18	gold quality
ganglionic eminence	UBERON:0004023	98.82	gold quality
cortical plate	UBERON:0005343	98.76	gold quality
middle frontal gyrus	UBERON:0002702	98.62	gold quality
stromal cell of endometrium	CL:0002255	98.45	gold quality
frontal pole	UBERON:0002795	98.45	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.27	gold quality
adrenal tissue	UBERON:0018303	98.18	gold quality
embryo	UBERON:0000922	98.14	gold quality
ventricular zone	UBERON:0003053	98.05	gold quality
cerebellar cortex	UBERON:0002129	97.88	gold quality
cerebellar hemisphere	UBERON:0002245	97.88	gold quality
cerebellum	UBERON:0002037	97.87	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.80	gold quality
endometrium epithelium	UBERON:0004811	97.69	gold quality
cingulate cortex	UBERON:0003027	96.91	gold quality
anterior cingulate cortex	UBERON:0009835	96.90	gold quality
left ovary	UBERON:0002119	96.81	gold quality
right frontal lobe	UBERON:0002810	96.80	gold quality
neocortex	UBERON:0001950	96.79	gold quality
prefrontal cortex	UBERON:0000451	96.76	gold quality
hypothalamus	UBERON:0001898	96.74	gold quality
frontal cortex	UBERON:0001870	96.73	gold quality
body of uterus	UBERON:0009853	96.73	gold quality
frontal lobe	UBERON:0016525	96.73	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.70	gold quality
substantia nigra pars compacta	UBERON:0001965	96.64	gold quality
islet of Langerhans	UBERON:0000006	96.63	gold quality
nucleus accumbens	UBERON:0001882	96.63	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.57	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6678	no	3.13
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, FLT3, MYC, SP1

miRNA regulators (miRDB)

87 targeting USP22, 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-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4739	99.84	65.25	1832

Literature-anchored findings (GeneRIF, showing 40)

• Altered mRNA expression is associated with therapy failure and death in patients multiple types of cancer. (PMID:15931389)
• ATXN7L3, USP22, & ENY2 are required cofactors for full transcriptional activity by nuclear receptors. The deubiquitinase activity of TFTC/STAGA HAT counteracts heterochromatin silencing & is a positive cofactor for in vivo nuclear receptor activation. (PMID:18206972)
• USP22 is a subunit of the SAGA transcriptional cofactor complex. It deubiquitylates histone H2B & is recruited to specific genes by activators like Myc. USP22 is needed for cell cycle progression. (PMID:18206973)
• biochemical analysis of the substrate specificity of USP22 reveals that it deubiquitylates histone H2A in addition to H2B (PMID:18469533)
• data suggest knockdown of USP22 expression by the aiRNA may down-regulate the expression of Mdm2 and cyclin E, resulting in the up-regulated expression of p53 and p21 and leading to cell cycle arrest and inhibition of human bladder EJ cell proliferation (PMID:20824490)
• The expression level of USP22 mRNA was significantly higher in primary colorectal cancer compared with non-cancerous mucosa tissues. (PMID:21039844)
• aberrant expression of USP22 may play an essential role in colorectal carcinogenesis and liver metastasis (PMID:21337558)
• Overexpression of USP22 may contribute to the progression of breast cancer and thus may serve as a new molecular marker to predict the prognosis of breast cancer patients. (PMID:21691749)
• simultaneous activation of USP22 and BMI-1 may associate with GC progression and therapy failure (PMID:21735131)
• Our study highlights the tight control of USP22 catalytic activity through an allosteric mechanism based on complex interactions with other subunits of the SAGA deubiquitination module. (PMID:21746879)
• USP22 plays a crucial role in tumor formation and growth by regulating cell proliferation with USP22-dependent signaling pathway. (PMID:21773699)
• show that USP22 affects the expression of p21 by altering far upstream element (FUSE)-binding protein 1 (FBP1) ubiquitination (PMID:21779003)
• USP22 may act as an oncogene in CRC as it positively regulates cell cycle via both BMI-1-mediated INK4a/ARF pathway and Akt signaling pathway. (PMID:21928107)
• RNAi-mediated knockdown of the ubiquitin hydrolase, USP22, results in 2-fold higher ubH2B, and 2-fold lower transcriptional elongation at IRF1. USP22 depletion also diminishes 3’-end cleavage/polyadenylation by 2- to 3-fold. (PMID:22067483)
• Data show that USP22 protein plays an essential role in esophageal squamous cell carcinoma (ESCC) progression and has clinical potentials as a biomarker and as an attractively therapeutic target for ESCC. (PMID:22447106)
• This is the first study that determines the relationship between USP22 expression and prognosis in oral squamous cell carcinoma. (PMID:22880026)
• The USP22 regulates the cell cycle via the c–Myc/cyclin D2 pathway and down–regulating p15 and p21 expression in HepG2 cell. (PMID:23217440)
• Sp1 is a crucial regulator of USP22 transcription. (PMID:23300749)
• USP22 plays an important role in NSCLC progression at the early stage, and that overexpression of USP22 in tumor tissues could be used as a potential prognostic marker for patients with early clinical stage of NSCLC (PMID:23361242)
• study identified the deubiquitinating enzyme ubiquitin-specific protease 22 (USP22), a component of the deubiquitinating module (DUBm) of the SAGA transcriptional coactivating complex, as a SIRT1-interacting partner (PMID:23382074)
• High USP22 expression is associated with papillary thyroid carcinoma. (PMID:23412977)
• Overexpression of USP22 may contribute to the progression of SDC and thus may serve as a new molecular marker to predict the prognosis of SDC patients (PMID:23664741)
• In this study, we investigated the protein expression of USP22 in different cervical tissues by immunohistochemical staining and analyze the correlation between USP22 level and clinicopathologic features including patient outco (PMID:23979981)
• Findings define USP22 as a critical effector of tumor progression, which drives lethal phenotypes. (PMID:24197134)
• High expression of USP22 was associated with Salivary Adenoid Cystic Carcinoma. (PMID:24466336)
• USP22 deubiquitinates and stabilizes NFATc2 protein levels thereby promoting IL2 expression. (PMID:24561192)
• USP22 overexpression may be associated with poor prognosis in patients with glioma (PMID:24573640)
• In the present study, a functional NLS and the minimal sequences required for the active targeting of USP22 to the nucleus were identified. (PMID:24802393)
• Data indicate that ubiquitin specific peptidase 22 (USP22)-mediated sirtuin 1 (SIRT1) deubiquitination inhibits STAT3 transcription factor acetylation and its transcriptional activation. (PMID:24969755)
• Results show that USP22 and FoxM1 are overexpressed in patients with pancreatic cancer and jointly involved in the development and progression of pancreatic cancerthe disease. (PMID:24993031)
• Overexpression of USP22 in pancreatic cancer promoted cytoskeletal remodeling, upregulated expression of transcription factors to promote epithelial-mesenchymal transition, and increased cellular invasion and migration. (PMID:25070659)
• Genetic studies indicate that Gcn5 and USP22 have important roles during development, which may presage important functions for these proteins in human diseases. [review] (PMID:25111486)
• USP22 is involved in the carcinogenesis of human pharyngeal squamous cell carcinoma. (PMID:25241842)
• Collectively, the present study demonstrated a new function of USP22 that induces autophagy, thus leading to the poor prognosis of pancreatic cancer. (PMID:25241857)
• The overexpression of USP22 was observed to attenuate TSAinduced apoptosis in HeLa cells. (PMID:25323692)
• USP22 may accelerate ovarian cancer cell cycle progression via synergizing with TGFB1 to regulate the TGFB1 downstream cell cycle pathway. (PMID:25369910)
• USP22 expression may play an important role in gastric carcinoma tissue. (PMID:25445209)
• ShRNA-mediated silencing of the ubiquitin-specific protease 22 gene restrained cell progression and affected the Akt pathway in nasopharyngeal carcinoma. (PMID:25482932)
• These results suggest that USP22 positively regulates RCAN1 levels, which would consequently affect diverse RCAN1-linked cellular processes. (PMID:25546086)
• USP22 is overexpressed in human NSCLC tissues and cell lines. USP22 silencing downregulates MDMX protein expression and activates the p53 pathway. (PMID:25547493)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp22	ENSDARG00000040407
mus_musculus	Usp22	ENSMUSG00000042506
rattus_norvegicus	Usp22	ENSRNOG00000032492
drosophila_melanogaster	not	FBGN0013717

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), 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 22 — Q9UPT9 (reviewed: Q9UPT9)

Alternative names: Deubiquitinating enzyme 22, Ubiquitin thioesterase 22, Ubiquitin-specific-processing protease 22

All UniProt accessions (5): Q9UPT9, J3QRV6, J3QS30, K7ERX6, K7ESK0

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinase that plays a role in several cellular processes including transcriptional regulation, cell cycle progression or innate immunity. As part of the transcription regulatory histone acetylation (HAT) complex SAGA, catalyzes the deubiquitination of both histones H2A and H2B, thereby acting as a transcriptional coactivator. Recruited to specific gene promoters by activators such as MYC, where it is required for transcription. Facilitates cell-cycle progression by stabilizing CCNB1 and antagonizing its proteasome-mediated degradation in a cell cycle-specific manner. Modulates cell cycle progression and apoptosis also by antagonizing TP53 transcriptional activation through deacetylase SIRT1 stabilization. Plays multiple roles in immunity and inflammation. Participates in antiviral response by deubiquitinating the importin KPNA2, leading to IRF3 nuclear translocation and subsequent type I interferon production. Acts as a central regulator of type III IFN signaling by negatively regulating STING1 activation and ubiquitination. Inhibits NLRP3 inflammasome activation by promoting NLRP3 degradation through ATG5-dependent autophagy. Deubiquitinates CD274 to induce its stabilization and thereby participates in maintenance of immune tolerance to self. Controls necroptotic cell death by regulating RIPK3 phosphorylation and ubiquitination. During bacterial infection, promotes pro-inflammatory response by targeting TRAF6 and removing its ‘Lys-48’-linked polyubiquitination.

Subunit / interactions. Component of some SAGA transcription coactivator-HAT complexes, at least composed of ATXN7, ATXN7L3, ENY2, GCN5L2, SUPT3H, TAF10, TRRAP and USP22. Within the SAGA complex, ATXN7L3, ENY2 and USP22 form a subcomplex required for histone deubiquitination. Interacts directly with ATXN7L3; leading to its recruitment to the SAGA complex. Interacts with ATXN7L3 and weakly with ATXN7L3B. Interacts with MED1.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Moderately expressed in various tissues including heart and skeletal muscle, and weakly expressed in lung and liver.

Post-translational modifications. Phosphorylated in G2/M phase, but not in G1 phase by CDK1. Ubiquitinated and subsequently degraded in a CDC20-dependent manner.

Similarity. Belongs to the peptidase C19 family. UBP8 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UPT9-1	1	yes
Q9UPT9-2	2

RefSeq proteins (1): NP_056091* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR001607	Znf_UBP	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050185	Ub_carboxyl-term_hydrolase	Family

Pfam: PF00443, PF02148

UniProt features (31 total): binding site 12, mutagenesis site 7, modified residue 3, sequence conflict 3, active site 2, chain 1, domain 1, zinc finger region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UPT9-F1	83.58	0.57

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): 185 (nucleophile); 479 (proton acceptor)

Ligand- & substrate-binding residues (12): 79; 84; 89; 93; 99; 112; 115; 23; 25; 63; 66; 76

Post-translational modifications (3): 129, 147, 237

Mutagenesis-validated functional residues (7):

Position	Phenotype
147	complete loss of cdk1-mediated phosphorylation; when associated with a-237.
164	complete loss of nuclear localization; when associated with a-165.
165	complete loss of nuclear localization; when associated with a-164.
185	complete loss of deubiquitinase activity.
237	complete loss of cdk1-mediated phosphorylation; when associated with a-147.
471	impairs its function as a positive modulator of androgen receptor transactivation; when associated with a-479.
479	impairs its function as a positive modulator of androgen receptor transactivation; when associated with a-471.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3214847	HATs acetylate histones
R-HSA-5689880	Ub-specific processing proteases

MSigDB gene sets: 254 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, MORF_UBE2I, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_REGULATION_OF_DNA_REPAIR, MORF_CCNI, BLALOCK_ALZHEIMERS_DISEASE_UP, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GLINSKY_CANCER_DEATH_UP

GO Biological Process (12): G2/M transition of mitotic cell cycle (GO:0000086), regulation of DNA repair (GO:0006282), regulation of transcription by RNA polymerase II (GO:0006357), proteolysis (GO:0006508), embryo development ending in birth or egg hatching (GO:0009792), protein deubiquitination (GO:0016579), positive regulation of type I interferon production (GO:0032481), regulation of RNA splicing (GO:0043484), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of mitotic cell cycle (GO:0045931), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338)

GO Molecular Function (12): transcription coactivator activity (GO:0003713), cysteine-type deubiquitinase activity (GO:0004843), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), histone H2B deubiquitinase activity (GO:0140936), histone H2A deubiquitinase activity (GO:0140950), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), histone H4 acetyltransferase activity (GO:0010485), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): SAGA complex (GO:0000124), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), transcription factor TFTC complex (GO:0033276)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitotic cell cycle	2
regulation of DNA-templated transcription	2
histone deubiquitinase activity	2
SAGA-type complex	2
cellular anatomical structure	2
mitotic cell cycle phase transition	1
cell cycle G2/M phase transition	1
DNA repair	1
regulation of DNA metabolic process	1
regulation of cellular response to stress	1
transcription by RNA polymerase II	1
protein metabolic process	1
embryo development	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
positive regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
RNA splicing	1
regulation of gene expression	1
regulation of primary metabolic process	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of mitotic cell cycle	1
positive regulation of cell cycle	1
cellular component organization	1
chromatin organization	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
transition metal ion binding	1
protein binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
histone acetyltransferase activity	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

1514 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP22	ATXN7L3	Q14CW9	991
USP22	ENY2	Q9NPA8	973
USP22	ATXN7	O15265	972
USP22	KAT2A	Q92830	843
USP22	USP13	Q92995	838
USP22	H2BC21	Q16778	827
USP22	TAF10	Q12962	757
USP22	ZUP1	Q96AP4	739
USP22	TADA3	O75528	735
USP22	H2BK1	A0A2R8Y619	728
USP22	H2BW2	P0C1H6	728
USP22	H2BC12L	P57053	728
USP22	H2BW1	Q7Z2G1	728
USP22	H2BC26	Q8N257	728
USP22	H2BC17	P23527	727
USP22	H2BC18	Q5QNW6	727

IntAct

103 interactions, top by confidence:

A	B	Type	Score
SGF29	NDC80	psi-mi:“MI:0914”(association)	0.840
ATXN7L1	USP22	psi-mi:“MI:0407”(direct interaction)	0.790
ATXN7L1	USP22	psi-mi:“MI:0915”(physical association)	0.790
TAF12	TAF4	psi-mi:“MI:0914”(association)	0.760
AASDHPPT	USP22	psi-mi:“MI:0915”(physical association)	0.740
USP22	AASDHPPT	psi-mi:“MI:0915”(physical association)	0.740
TRRAP	ATXN7	psi-mi:“MI:0914”(association)	0.740
PRKACA	VAPB	psi-mi:“MI:0914”(association)	0.730
ATXN7L3	USP27X	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
ENPP6	SCAMP1	psi-mi:“MI:0914”(association)	0.640
TMED2	ATP9A	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
FUBP1	USP22	psi-mi:“MI:0915”(physical association)	0.580
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
CREB3L1	AP3B1	psi-mi:“MI:0914”(association)	0.530
LDLRAD4	WWP2	psi-mi:“MI:0914”(association)	0.530
RNF19B	PIK3R2	psi-mi:“MI:0914”(association)	0.530
CTDSP1	CTDSP2	psi-mi:“MI:0914”(association)	0.530

BioGRID (373): AASDHPPT (Two-hybrid), USP22 (Affinity Capture-RNA), USP22 (Affinity Capture-RNA), USP22 (Affinity Capture-MS), USP22 (Affinity Capture-MS), USP22 (Affinity Capture-MS), USP22 (Affinity Capture-MS), USP22 (Affinity Capture-MS), USP22 (Affinity Capture-MS), USP22 (Affinity Capture-MS), USP22 (Affinity Capture-MS), USP22 (Affinity Capture-MS), USP22 (Affinity Capture-Western), RCAN1 (Affinity Capture-Western), USP22 (Two-hybrid)

ESM2 similar proteins: A0A0G2JTR4, A4FUN7, A5D9H7, A5WWB0, A6H8I0, A6NNY8, A6QNS3, C0HB46, D0RB01, E1C1R4, F1M625, O24454, O75317, P09851, P0C8Z3, P20936, P50904, P62068, P62069, Q09LZ8, Q12979, Q16288, Q3TIX9, Q52KZ6, Q53GS9, Q5DU02, Q5F415, Q5F450, Q5IFJ9, Q5IS37, Q5IS82, Q5M981, Q5R573, Q5R761, Q5R8I6, Q5RBQ4, Q5RDP3, Q5SSL4, Q60969, Q6DCJ1

Diamond homologs: A0A0R4IB93, A0JM59, A5PMR2, A5PN09, A6NNY8, A6QNM7, A7Z056, B1AY13, B1WBD7, D2HBJ8, D6RBM5, E1C213, E7F6T8, E9Q9U0, F6Z5C0, F8VPU6, F8VPZ3, M9PD06, O00507, O22207, O60079, O74442, O94269, O94966, O96612, P0C7I0, P0C8Z3, P0CAQ1, P35125, P39538, P40453, P51784, P53874, P55824, P70398, Q01988, Q09738, Q0V9G5, Q28CN3, Q2HJE4

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
FLT3	“up-regulates quantity by expression”	USP22	“transcriptional regulation”
MYC	“up-regulates quantity by expression”	USP22	“transcriptional regulation”
USP22	“up-regulates quantity by stabilization”	SIRT1	deubiquitination
USP22	“form complex”	“SAGA complex”	binding
CDK1	“up-regulates activity”	USP22	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
HATs acetylate histones	10	8.4×	2e-04
Chromatin organization	9	7.8×	6e-04
Chromatin modifying enzymes	9	6.9×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of DNA repair	12	26.9×	1e-11
regulation of RNA splicing	11	19.6×	4e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2192 predictions. Top by Δscore:

Variant	Effect	Δscore
17:21004197:CGCA:C	donor_loss	1.0000
17:21004198:GCA:G	donor_loss	1.0000
17:21004199:CA:C	donor_loss	1.0000
17:21004200:A:AC	donor_gain	1.0000
17:21004200:A:C	donor_loss	1.0000
17:21004200:AC:A	donor_gain	1.0000
17:21004201:C:CC	donor_gain	1.0000
17:21004201:CC:C	donor_gain	1.0000
17:21004201:CCCTT:C	donor_gain	1.0000
17:21004220:T:TA	donor_gain	1.0000
17:21004349:TAC:T	acceptor_gain	1.0000
17:21004351:CCTAG:C	acceptor_gain	1.0000
17:21004353:T:G	acceptor_loss	1.0000
17:21004355:G:C	acceptor_gain	1.0000
17:21004355:G:GC	acceptor_gain	1.0000
17:21004358:C:CT	acceptor_gain	1.0000
17:21004359:A:T	acceptor_gain	1.0000
17:21004924:TTAC:T	donor_loss	1.0000
17:21004925:TACT:T	donor_loss	1.0000
17:21004926:A:AC	donor_gain	1.0000
17:21004927:C:CA	donor_gain	1.0000
17:21004927:CT:C	donor_gain	1.0000
17:21004927:CTT:C	donor_gain	1.0000
17:21004927:CTTG:C	donor_gain	1.0000
17:21004927:CTTGT:C	donor_gain	1.0000
17:21004986:CTTTG:C	acceptor_gain	1.0000
17:21004987:TTTG:T	acceptor_gain	1.0000
17:21004987:TTTGC:T	acceptor_loss	1.0000
17:21004988:TTG:T	acceptor_gain	1.0000
17:21004989:TG:T	acceptor_gain	1.0000

AlphaMissense

3508 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:21003060:A:C	Y517D	1.000
17:21003065:A:G	L515P	1.000
17:21003065:A:T	L515Q	1.000
17:21003068:A:C	L514W	1.000
17:21003072:A:G	Y513H	1.000
17:21004202:C:T	G512E	1.000
17:21004203:C:A	G512W	1.000
17:21004203:C:G	G512R	1.000
17:21004203:C:T	G512R	1.000
17:21004217:A:T	V507D	1.000
17:21004241:A:T	I499N	1.000
17:21004249:A:C	D496E	1.000
17:21004249:A:T	D496E	1.000
17:21004250:T:A	D496V	1.000
17:21004250:T:C	D496G	1.000
17:21004250:T:G	D496A	1.000
17:21004251:C:A	D496Y	1.000
17:21004251:C:G	D496H	1.000
17:21004255:A:C	C494W	1.000
17:21004257:A:G	C494R	1.000
17:21004264:C:A	W491C	1.000
17:21004264:C:G	W491C	1.000
17:21004265:C:G	W491S	1.000
17:21004266:A:G	W491R	1.000
17:21004266:A:T	W491R	1.000
17:21004283:C:G	R485P	1.000
17:21004298:T:C	Y480C	1.000
17:21004299:A:C	Y480D	1.000
17:21004299:A:G	Y480H	1.000
17:21004299:A:T	Y480N	1.000

dbSNP variants (sampled 300 via entrez): RS1000026081 (17:21009594 T>C), RS1000080816 (17:21035526 C>A), RS1000093945 (17:20999182 A>G), RS1000217579 (17:21035814 A>G), RS1000218647 (17:21000643 G>A), RS1000223836 (17:21039852 G>A), RS1000226903 (17:21003474 T>TCC), RS1000264946 (17:21010474 C>T), RS1000296580 (17:21025340 T>A,C), RS1000366433 (17:21008678 C>T), RS1000423527 (17:21040713 G>A), RS1000483548 (17:21042970 G>A,C,T), RS1000485878 (17:21034230 A>G), RS1000550138 (17:21001971 A>T), RS1000556494 (17:21036753 G>A,T)

Disease associations

OMIM: gene MIM:612116 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004863_82	Mosquito bite size	4.000000e-06
GCST005951_14	Body mass index	5.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008378	mosquito bite reaction size measurement
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291597 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases methylation, affects expression	3
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Vehicle Emissions	increases abundance, affects expression, increases reaction	2
Ozone	decreases expression, increases oxidation, increases abundance, affects cotreatment	2
Particulate Matter	increases abundance, affects expression, increases reaction	2
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
alpha phellandrene	increases expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression, increases oxidation	1
trichostatin A	decreases expression	1
sodium arsenite	decreases expression	1
pinosylvin	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases oxidation	1
Benzo(a)pyrene	increases methylation	1
Methotrexate	decreases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Volatile Organic Compounds	affects cotreatment, decreases expression, increases oxidation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5251111	Binding	Inhibition of human USP22 (1 to 525 residues) expressed in Sf9 cells using ubiquitin rhodamine 110 as substrate assessed as remaining enzyme activity at 10 to 50 uM by fluorometric assay	Discovery and Characterization of BAY-805, a Potent and Selective Inhibitor of Ubiquitin-Specific Protease USP21. — J Med Chem

Cellosaurus cell lines

8 cell lines: 8 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2KK	Abcam HeLa USP22 KO	Cancer cell line	Female
CVCL_B8RJ	Abcam HCT 116 USP22 KO	Cancer cell line	Male
CVCL_B9TZ	Abcam A-549 USP22 KO	Cancer cell line	Male
CVCL_D6B8	HyCyte HCCLM3 KO-hUSP22	Cancer cell line	Male
CVCL_E1DM	Ubigene THP-1 USP22 KO	Cancer cell line	Male
CVCL_E1M6	HyCyte MDA-MB-231 KO-hUSP22	Cancer cell line	Female
CVCL_TW76	HAP1 USP22 (-) 1	Cancer cell line	Male
CVCL_TW77	HAP1 USP22 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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