USP36

Summary

USP36 (ubiquitin specific peptidase 36, HGNC:20062) is a protein-coding gene on chromosome 17q25.3, encoding Ubiquitin carboxyl-terminal hydrolase 36 (Q9P275). Deubiquitinase essential for the regulation of nucleolar structure and function. It is a common-essential gene (DepMap: required in 99.4% of cancer cell lines).

This gene encodes a member of the peptidase C19 or ubiquitin-specific protease family of cysteine proteases. Members of this family remove ubiquitin molecules from polyubiquitinated proteins. The encoded protein may deubiquitinate and stabilize the transcription factor c-Myc, also known as MYC, an important oncoprotein known to be upregulated in most human cancers. The encoded protease may also regulate the activation of autophagy. This gene exhibits elevated expression in some breast and lung cancers.

Source: NCBI Gene 57602 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 270 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.4% of screened cell lines (common-essential)
• MANE Select transcript: NM_001385174

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20062
Approved symbol	USP36
Name	ubiquitin specific peptidase 36
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1453, FLJ12851
Ensembl gene	ENSG00000055483
Ensembl biotype	protein_coding
OMIM	612543
Entrez	57602

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 20 protein_coding, 7 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000312010, ENST00000449938, ENST00000542802, ENST00000586066, ENST00000586531, ENST00000586896, ENST00000587010, ENST00000587379, ENST00000587783, ENST00000588086, ENST00000588130, ENST00000588365, ENST00000588467, ENST00000589225, ENST00000589254, ENST00000589424, ENST00000590312, ENST00000590546, ENST00000591052, ENST00000591942, ENST00000592231, ENST00000592275, ENST00000592326, ENST00000592907, ENST00000693020, ENST00000865525, ENST00000865526, ENST00000865527, ENST00000927226, ENST00000927227, ENST00000927228, ENST00000947940

RefSeq mRNA: 13 — MANE Select: NM_001385174 NM_001321291, NM_001385169, NM_001385170, NM_001385171, NM_001385172, NM_001385173, NM_001385174, NM_001385175, NM_001385176, NM_001385177, NM_001385178, NM_001385179, NM_001385180

CCDS: CCDS32755

Canonical transcript exons

ENST00000449938 — 21 exons

Exon	Start	End
ENSE00001033869	78838587	78838750
ENSE00001297400	78806959	78807636
ENSE00001298564	78803385	78803978
ENSE00001298599	78799667	78799768
ENSE00001310548	78806156	78806286
ENSE00001310573	78802324	78802535
ENSE00001311935	78798908	78799023
ENSE00002248591	78835280	78835501
ENSE00002265404	78798400	78798551
ENSE00002275689	78836111	78836372
ENSE00002303284	78828897	78829007
ENSE00002310214	78821937	78822004
ENSE00003465529	78818667	78818778
ENSE00003624013	78827245	78827347
ENSE00003678915	78814412	78814552
ENSE00003688164	78813773	78813873
ENSE00003735803	78819930	78820012
ENSE00003753992	78820991	78821061
ENSE00003784064	78812860	78813001
ENSE00003925273	78840736	78840814
ENSE00003934623	78795652	78797879

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 95.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.0441 / max 316.2628, expressed in 1811 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168477	26.6396	1811
168478	1.7942	815
168479	0.3615	131
168474	0.0859	43
168475	0.0609	19
168469	0.0527	16
168473	0.0493	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	95.51	gold quality
adenohypophysis	UBERON:0002196	95.08	gold quality
left ovary	UBERON:0002119	94.99	gold quality
right ovary	UBERON:0002118	94.27	gold quality
left uterine tube	UBERON:0001303	93.85	gold quality
omental fat pad	UBERON:0010414	93.83	gold quality
peritoneum	UBERON:0002358	93.80	gold quality
body of pancreas	UBERON:0001150	93.61	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.48	gold quality
cerebellar hemisphere	UBERON:0002245	93.46	gold quality
skin of leg	UBERON:0001511	93.44	gold quality
skin of abdomen	UBERON:0001416	93.40	gold quality
cerebellar cortex	UBERON:0002129	93.35	gold quality
pituitary gland	UBERON:0000007	93.20	gold quality
mucosa of stomach	UBERON:0001199	93.06	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.02	gold quality
tendon of biceps brachii	UBERON:0008188	92.67	gold quality
left lobe of thyroid gland	UBERON:0001120	92.63	gold quality
tibial nerve	UBERON:0001323	92.56	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.37	gold quality
ovary	UBERON:0000992	92.15	gold quality
body of uterus	UBERON:0009853	92.13	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.09	gold quality
upper lobe of left lung	UBERON:0008952	92.05	gold quality
right lobe of thyroid gland	UBERON:0001119	92.04	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.04	gold quality
lower esophagus	UBERON:0013473	92.02	gold quality
right lung	UBERON:0002167	91.96	gold quality
endocervix	UBERON:0000458	91.95	gold quality
thyroid gland	UBERON:0002046	91.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.09

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 31)

• DUB-1 is present ubuquitously within cells and has deubiitinating enzyme activity in vivo and in vitro. (PMID:15254734)
• indentification of deubiquitinating enzyme activity of USP36 by analyzing its capability to cleave the ubiquitin (PMID:15809067)
• USP36 is overexpressed in ovarian cancer compared to normal ovary and its transcripts were identified in ascites and serum of ovarian cancer patients (PMID:18566677)
• Results suggest that by deubiquitylating various nucleolar substrate proteins including nucleophosmin/B23 and fibrillarin, USP36 plays a crucial role in regulating the structure and function of nucleoli. (PMID:19208757)
• Data suggest that nucleophosmin/B23 recruits USP36 to nucleoli, thereby serving as a platform for the regulation of nucleolar protein functions through ubiquitylation/deubiquitylation. (PMID:19679658)
• Study identified a deubiquitinating enzyme USP36 that regulates the protein stability of SOD2. (PMID:21268071)
• USP36 controls selective autophagy activation in Drosophila and in human cells. (PMID:22622177)
• The most significantly associated SNPs to type 2 diabetes mellitus in this study are expression SNPs to the lymphocyte antigen 75 gene, the ubiquitin-specific peptidase 36 gene, and the phosphatidylinositol transfer protein, cytoplasmic 1 gene. (PMID:22865700)
• Recently, much progress has been made in understanding the physiological functions of cytokine-inducible DUBs such as DUB-1, DUB-2, and DUB-3/USP17, in regulation of cell proliferation and apoptosis in lymphocytes. [review] (PMID:23773437)
• USP36 is a crucial and bono fide deubiquitinating enzyme controlling c-Myc’s nucleolar degradation pathway (PMID:25775507)
• USP36 actions extend beyond TrkA because the presence of USP36 interferes with Nedd4-2-dependent Kv7.2/3 channel regulation. (PMID:27445338)
• Together, our results reveal USP36 as a novel H2B deubiquitinase and shed light on its additional functions in regulating gene expression. (PMID:29274341)
• USP36 regulates PME-1 as a DUB and participates in the ERK and Akt signaling pathways (PMID:29577269)
• USP36 overexpression decreased ischemia-induced apoptosis and oxidative stress in human renal tubular HK-2cells. The protein levels of c-Myc and SOD2 were declined in ischemic HK-2cells with enhanced ubiquitination. USP36 overexpression stabilized c-Myc and SOD2 by preventing ischemia-induced ubiquitination of both proteins. (PMID:30975468)
• USP36 as regulator for the Parkin-dependent mitophagy at least in part via the Beclin-1-ATG14L pathway. (PMID:31550441)
• The deubiquitinase USP36 Regulates DNA replication stress and confers therapeutic resistance through PrimPol stabilization. (PMID:33237263)
• The deubiquitinase USP36 promotes snoRNP group SUMOylation and is essential for ribosome biogenesis. (PMID:33852194)
• Processing of the ribosomal ubiquitin-like fusion protein FUBI-eS30/FAU is required for 40S maturation and depends on USP36. (PMID:34318747)
• USP36 promotes tumor growth of non-small cell lung cancer via increasing KHK-A expression by regulating c-MYC-hnRNPH1/H2 axis. (PMID:35133629)
• Gene Signature and Prognostic Value of Ubiquitin-Specific Proteases Members in Hepatocellular Carcinoma and Explored the Immunological Role of USP36. (PMID:35748266)
• DUB1 suppresses Hippo signaling by modulating TAZ protein expression in gastric cancer. (PMID:35820928)
• CircRNA circUSP36 impairs the stability of NEDD4L mRNA through recruiting PTBP1 to enhance ULK1-mediated autophagic granulosa cell death. (PMID:35964538)
• USP36 facilitates esophageal squamous carcinoma progression via stabilizing YAP. (PMID:36470870)
• The ubiquitin-specific protease USP36 SUMOylates EXOSC10 and promotes the nucleolar RNA exosome function in rRNA processing. (PMID:36912080)
• The Ubiquitin-specific Protease USP36 Associates with the Microprocessor Complex and Regulates miRNA Biogenesis by SUMOylating DGCR8. (PMID:36950067)
• USP36 plays an oncogenic role in colorectal cancer cells. (PMID:38215036)
• Germline USP36 Mutation Confers Resistance to EGFR-TKIs by Upregulating MLLT3 Expression in Patients with Non-Small Cell Lung Cancer. (PMID:38261467)
• USP36 inhibits apoptosis by deubiquitinating cIAP1 and survivin in colorectal cancer cells. (PMID:38876304)
• USP36 regulates the proliferation, survival, and differentiation of hFOB1.19 osteoblast. (PMID:39152465)
• USP36 promotes tumorigenesis and tamoxifen resistance in breast cancer by deubiquitinating and stabilizing ERalpha. (PMID:39215346)
• USP36 SUMOylates Las1L and Promotes Its Function in Pre-Ribosomal RNA ITS2 Processing. (PMID:39356143)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp36	ENSDARG00000032327
mus_musculus	Usp36	ENSMUSG00000033909
rattus_norvegicus	Usp36	ENSRNOG00000028255

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), USP10 (ENSG00000103194), USP31 (ENSG00000103404), USP42 (ENSG00000106346), USP5 (ENSG00000111667), USP4 (ENSG00000114316), USP9Y (ENSG00000114374), USP34 (ENSG00000115464), USP35 (ENSG00000118369), USP45 (ENSG00000123552), USP22 (ENSG00000124422), USP9X (ENSG00000124486), USP6 (ENSG00000129204), USP29 (ENSG00000131864), USP26 (ENSG00000134588), USP30 (ENSG00000135093), 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 36 — Q9P275 (reviewed: Q9P275)

Alternative names: Deubiquitinating enzyme 36, Ubiquitin thioesterase 36, Ubiquitin-specific-processing protease 36

All UniProt accessions (18): A0A075B784, A0A8I5QJW4, E9PEW0, Q9P275, K7EIH0, K7EIT7, K7EJI3, K7EKL7, K7EKN3, K7ELR5, K7ELT3, K7EMM6, K7EPT1, K7EQS0, K7ERC1, K7ERP8, Q8IXW9, U3KQ92

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinase essential for the regulation of nucleolar structure and function. Required for cell and organism viability. Plays an important role in ribosomal RNA processing and protein synthesis, which is mediated, at least in part, through deubiquitination of DHX33, NPM1 and FBL, regulating their protein stability. Functions as a transcriptional repressor by deubiquiting histone H2B at the promoters of genes critical for cellular differentiation, such as CDKN1A, thereby preventing histone H3 ‘Lys-4’ trimethylation (H3K4). Specifically deubiquitinates MYC in the nucleolus, leading to prevent MYC degradation by the proteasome: acts by specifically interacting with isoform 3 of FBXW7 (FBW7gamma) in the nucleolus and counteracting ubiquitination of MYC by the SCF(FBW7) complex. In contrast, it does not interact with isoform 1 of FBXW7 (FBW7alpha) in the nucleoplasm. Interacts to and regulates the actions of E3 ubiquitin-protein ligase NEDD4L over substrates such as NTRK1, KCNQ2 and KCNQ3, affecting their expression an functions. Deubiquitinates SOD2, regulates SOD2 protein stability. Deubiquitinase activity is required to control selective autophagy activation by ubiquitinated proteins. Promotes CEP63 stabilization through ‘Lys-48’-linked deubiquitination leading to increased stability. Acts as a SUMO ligase to promote EXOSC10 sumoylation critical for the nucleolar RNA exosome function in rRNA processing. Binds to pre-rRNAs.

Subunit / interactions. Interacts with isoform 3 of FBXW7; the interaction inhibits MYC degradation induced by SCF(FBW7) complex. Interacts with NTRK1; USP36 does not deubiquitinate NTRK1. Interacts with NEDD4L (via domains WW1, 3 and 4); the interaction inhibits ubiquitination of, at least, NTRK1, KCNQ2 and KCNQ3 by NEDD4L. Interacts (via C-terminus) with EXOSC10 (via C-terminus); the interaction is facilitated by the association with RNA and promotes sumoylation of EXOSC10.

Subcellular location. Nucleus. Nucleolus. Cytoplasm.

Tissue specificity. Broadly expressed.

Post-translational modifications. Polyubiquitinated by NEDD4L, no effect on USP36 protein levels. Both proteins interact with and regulate each other’s ubiquitination levels.

Induction. Down-regulated by ribosomal stress (at protein level).

Similarity. Belongs to the peptidase C19 family.

RefSeq proteins (13): NP_001308220, NP_001372098, NP_001372099, NP_001372100, NP_001372101, NP_001372102, NP_001372103, NP_001372104, NP_001372105, NP_001372106, NP_001372107, NP_001372108, NP_001372109 (=MANE)

Domains & families (InterPro)

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

Pfam: PF00443

UniProt features (77 total): strand 19, compositionally biased region 14, helix 12, modified residue 9, sequence variant 8, region of interest 4, turn 4, active site 2, sequence conflict 2, chain 1, domain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8BS9	X-RAY DIFFRACTION	1.9
8BS3	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P275-F1	55.88	0.23

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): 131 (nucleophile); 382 (proton acceptor)

Post-translational modifications (9): 429, 464, 546, 582, 667, 682, 713, 742, 952

Mutagenesis-validated functional residues (1):

Position	Phenotype
131	abolishes deubiquitinase activity. no effect on ntrk1 ubiquitination levels.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 222 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RIBOSOME_BIOGENESIS, GOBP_REGULATION_OF_AUTOPHAGY, MODULE_255, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_PROTEIN_TARGETING, MODULE_317, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, NAGASHIMA_NRG1_SIGNALING_UP, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, BEIER_GLIOMA_STEM_CELL_DN, GOBP_MACROAUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_AUTOPHAGY

GO Biological Process (12): chromatin organization (GO:0006325), proteolysis (GO:0006508), nucleolus organization (GO:0007000), negative regulation of macroautophagy (GO:0016242), protein deubiquitination (GO:0016579), regulation of protein stability (GO:0031647), regulation of apoptotic process (GO:0042981), protein stabilization (GO:0050821), regulation of mitophagy (GO:1901524), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), regulation of rRNA processing (GO:2000232), chromatin remodeling (GO:0006338)

GO Molecular Function (9): RNA binding (GO:0003723), cysteine-type deubiquitinase activity (GO:0004843), transferase activity (GO:0016740), histone H2B deubiquitinase activity (GO:0140936), K48-linked deubiquitinase activity (GO:1990380), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of macroautophagy	2
deubiquitinase activity	2
catalytic activity	2
nuclear lumen	2
cellular component organization	1
protein metabolic process	1
nucleus organization	1
negative regulation of autophagy	1
macroautophagy	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
regulation of biological quality	1
apoptotic process	1
regulation of programmed cell death	1
regulation of protein stability	1
mitophagy	1
regulation of autophagy of mitochondrion	1
rRNA processing	1
regulation of gene expression	1
regulation of RNA metabolic process	1
chromatin organization	1
nucleic acid binding	1
cysteine-type peptidase activity	1
histone deubiquitinase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cytoplasm	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

1034 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP36	ZUP1	Q96AP4	797
USP36	UTP14A	Q9BVJ6	702
USP36	USP28	Q96RU2	650
USP36	H2BC21	Q16778	591
USP36	USP25	Q9UHP3	568
USP36	USP30	Q70CQ3	560
USP36	MYC	P01106	557
USP36	USP13	Q92995	519
USP36	OTUD6B	Q8N6M0	504
USP36	USP5	P45974	491
USP36	JOSD1	Q15040	471
USP36	JOSD2	Q8TAC2	470
USP36	OTUB1	Q96FW1	454
USP36	ATG14	Q6ZNE5	453
USP36	ZSCAN4	Q8NAM6	446

IntAct

92 interactions, top by confidence:

A	B	Type	Score
DHX33	USP36	psi-mi:“MI:0915”(physical association)	0.740
NPM1	MPHOSPH10	psi-mi:“MI:0914”(association)	0.610
NT5E	SCAMP1	psi-mi:“MI:0914”(association)	0.530
N	NOP56	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
TMEM31	PSMD11	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
USP36	NPM1	psi-mi:“MI:0914”(association)	0.530
PTGES3	AIP	psi-mi:“MI:0914”(association)	0.530
ABT1	ZNF316	psi-mi:“MI:0914”(association)	0.530
LIN28B	ELAVL2	psi-mi:“MI:0914”(association)	0.530
MAGEB2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
RPL13	RRP8	psi-mi:“MI:0914”(association)	0.530
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
NPM1	WDR46	psi-mi:“MI:0914”(association)	0.480
RPL10	RPS6	psi-mi:“MI:0914”(association)	0.350
HNRNPU		psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
USP36	NPM1	psi-mi:“MI:0914”(association)	0.350
USP36	STK25	psi-mi:“MI:0914”(association)	0.350
N	RBM47	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
LDLRAD1	GXYLT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (728): MYC (Biochemical Activity), MYC (Affinity Capture-Western), USP36 (Affinity Capture-Western), MYC (Reconstituted Complex), USP36 (Affinity Capture-Western), FBXW7 (Affinity Capture-Western), DHX33 (Affinity Capture-MS), KIAA0232 (Affinity Capture-MS), NPM1 (Affinity Capture-MS), PJA1 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), USP36 (Affinity Capture-MS), USP36 (Affinity Capture-MS), USP36 (Biochemical Activity), USP36 (Proximity Label-MS)

ESM2 similar proteins: A5PK23, A7MB40, A7XYI6, B1AQJ2, B1AZP2, E7F888, E9Q0S6, J7FCF0, O00257, O43182, O55187, O95402, O95886, P30658, P55198, P78312, P97838, P97839, Q04891, Q0P5V2, Q3B8N7, Q3U108, Q4G0F8, Q6PFD5, Q6PJG2, Q7TN02, Q7TT28, Q80VC9, Q80Z38, Q86V15, Q8C5R2, Q8CGB6, Q8K4J6, Q8N1G1, Q8TF72, Q8WYL5, Q90YL3, Q90YY5, Q969V6, Q99P96

Diamond homologs: A4FUN7, A5PMR2, A5PN09, A6H8I0, A6NNY8, A6QNM7, A6QR55, A7Z056, A8MUK1, B1AY15, B1WBD7, B2GUZ1, B2RQC2, C9JJH3, C9JLJ4, C9JPN9, C9JVI0, D3ZU96, D6R901, D6R9N7, D6RA61, D6RBM5, D6RBQ6, D6RCP7, D6RJB6, E1B9W9, F6Z5C0, M9PD06, O22207, O60079, O75604, O94966, P0C8Z3, P35123, P39538, P40818, P50102, P51784, Q09738, Q0WX57

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
USP36	“up-regulates quantity by stabilization”	NPM1	deubiquitination
USP36	“up-regulates quantity by stabilization”	FBL	deubiquitination
USP36	“up-regulates quantity by stabilization”	EZH2	deubiquitination
USP36	“up-regulates quantity by stabilization”	DHX33	deubiquitination
USP36	“up-regulates quantity by stabilization”	SOD2	deubiquitination
USP36	“up-regulates quantity by stabilization”	“RNA Polymerase I”	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 119 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
rRNA modification in the nucleus and cytosol	7	18.5×	2e-05
Major pathway of rRNA processing in the nucleolus and cytosol	17	14.8×	4e-13
rRNA processing in the nucleus and cytosol	6	13.6×	2e-04
Peptide chain elongation	7	12.5×	1e-04
Viral mRNA Translation	7	12.5×	1e-04
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	7	12.4×	1e-04
rRNA processing	6	12.4×	2e-04
SARS-CoV-1-host interactions	5	12.4×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
ribosomal large subunit biogenesis	5	20.7×	6e-04
ribosomal small subunit biogenesis	9	19.1×	5e-07
cytoplasmic translation	8	13.8×	2e-05
rRNA processing	9	11.9×	2e-05
negative regulation of translation	6	11.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	193
Likely benign	30
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

4034 predictions. Top by Δscore:

Variant	Effect	Δscore
17:78799024:C:CC	acceptor_gain	1.0000
17:78812863:T:A	donor_gain	1.0000
17:78813002:C:CC	acceptor_gain	1.0000
17:78813792:AGG:A	donor_gain	1.0000
17:78813884:C:CT	acceptor_gain	1.0000
17:78813889:A:C	acceptor_gain	1.0000
17:78813892:T:C	acceptor_gain	1.0000
17:78813892:T:TC	acceptor_gain	1.0000
17:78813896:A:T	acceptor_gain	1.0000
17:78814406:TCTCA:T	donor_loss	1.0000
17:78814407:CTCAC:C	donor_loss	1.0000
17:78814409:CACC:C	donor_loss	1.0000
17:78814411:C:CG	donor_loss	1.0000
17:78814548:ACATC:A	acceptor_gain	1.0000
17:78814549:CATC:C	acceptor_gain	1.0000
17:78814549:CATCC:C	acceptor_gain	1.0000
17:78814551:TC:T	acceptor_gain	1.0000
17:78814552:CC:C	acceptor_gain	1.0000
17:78814553:C:CC	acceptor_gain	1.0000
17:78814557:T:C	acceptor_gain	1.0000
17:78814557:T:TC	acceptor_gain	1.0000
17:78814566:C:CT	acceptor_gain	1.0000
17:78814567:A:T	acceptor_gain	1.0000
17:78818593:A:AC	donor_gain	1.0000
17:78818600:T:A	donor_gain	1.0000
17:78818775:GCAT:G	acceptor_gain	1.0000
17:78818776:CAT:C	acceptor_gain	1.0000
17:78818776:CATC:C	acceptor_gain	1.0000
17:78818777:ATC:A	acceptor_loss	1.0000
17:78818778:TC:T	acceptor_loss	1.0000

AlphaMissense

3590 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:78813842:T:A	D399V	1.000
17:78813858:A:G	W394R	1.000
17:78813858:A:T	W394R	1.000
17:78814459:G:C	H373D	1.000
17:78814467:A:T	V370D	1.000
17:78814543:A:C	Y345D	1.000
17:78818697:A:C	F331L	1.000
17:78818697:A:T	F331L	1.000
17:78818699:A:G	F331L	1.000
17:78818702:G:T	R330S	1.000
17:78818751:C:A	K313N	1.000
17:78818751:C:G	K313N	1.000
17:78818753:T:C	K313E	1.000
17:78818758:G:T	A311D	1.000
17:78818776:C:G	C305S	1.000
17:78818777:A:G	C305R	1.000
17:78818777:A:T	C305S	1.000
17:78819935:A:C	C302W	1.000
17:78819936:C:G	C302S	1.000
17:78819936:C:T	C302Y	1.000
17:78819937:A:G	C302R	1.000
17:78819937:A:T	C302S	1.000
17:78819943:A:C	Y300D	1.000
17:78819943:A:G	Y300H	1.000
17:78821045:G:C	C258W	1.000
17:78821046:C:G	C258S	1.000
17:78821046:C:T	C258Y	1.000
17:78821047:A:G	C258R	1.000
17:78821047:A:T	C258S	1.000
17:78821054:G:C	C255W	1.000

dbSNP variants (sampled 300 via entrez): RS1000051845 (17:78822350 A>C), RS1000068866 (17:78803000 G>A), RS1000069740 (17:78835647 G>A,T), RS1000094026 (17:78789058 G>A,T), RS1000144261 (17:78794198 G>A), RS1000195308 (17:78825564 C>T), RS1000319274 (17:78832004 A>G), RS1000328801 (17:78832224 C>G,T), RS1000353187 (17:78817134 G>A,C), RS1000420130 (17:78802814 T>C), RS1000435151 (17:78787114 T>C), RS1000518909 (17:78831645 T>C), RS1000528194 (17:78789209 A>G), RS1000534302 (17:78826732 G>A), RS1000562103 (17:78793512 C>T)

Disease associations

OMIM: gene MIM:612543 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST006414_37	Atrial fibrillation	4.000000e-08
GCST006479_51	Diverticular disease	1.000000e-07
GCST006979_256	Heel bone mineral density	3.000000e-09
GCST007096_61	Pulse pressure	2.000000e-06
GCST007099_18	Systolic blood pressure	1.000000e-08
GCST007267_247	Systolic blood pressure	2.000000e-08
GCST010662_17	Systolic blood pressure	4.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009959	diverticular disease
EFO:0009270	heel bone mineral density
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630861 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3744797	USP36		0.00	0

ChEMBL bioactivities

38 potent at pChembl≥5 of 38 total, top 38 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.70	IC50	198	nM	CHEMBL5303447
6.48	IC50	329	nM	CHEMBL5402536
6.47	IC50	335	nM	CHEMBL5425763
6.47	IC50	340	nM	CHEMBL5440446
6.44	IC50	365	nM	CHEMBL5395399
6.39	IC50	407	nM	CHEMBL5426200
6.29	IC50	507	nM	CHEMBL5405199
6.26	IC50	553	nM	CHEMBL5430481
6.25	IC50	556	nM	CHEMBL5398825
6.25	IC50	560	nM	CHEMBL5416528
6.23	IC50	587	nM	CHEMBL5419354
6.18	IC50	666	nM	CHEMBL5398708
6.17	IC50	669	nM	CHEMBL5424112
6.16	IC50	689	nM	CHEMBL5431635
6.13	IC50	749	nM	CHEMBL5408990
6.12	IC50	764	nM	CHEMBL5435107
6.09	IC50	816	nM	CHEMBL5400602
6.09	IC50	820	nM	CHEMBL5399861
6.08	IC50	826	nM	CHEMBL5431379
6.07	IC50	849	nM	CHEMBL5403255
6.06	IC50	868	nM	CHEMBL5398678
6.05	IC50	898	nM	CHEMBL5436187
6.05	IC50	900	nM	CHEMBL5416230
6.04	IC50	923	nM	CHEMBL5432156
6.02	IC50	961	nM	CHEMBL5414618
6.02	IC50	961	nM	CHEMBL5408951
6.02	IC50	964	nM	CHEMBL5423451
6.00	IC50	989	nM	CHEMBL5436483
6.00	IC50	1011	nM	CHEMBL5394917
6.00	IC50	1011	nM	CHEMBL5425352
5.98	IC50	1046	nM	CHEMBL5413932
5.98	IC50	1046	nM	CHEMBL5422372
5.97	IC50	1078	nM	CHEMBL5426495
5.79	IC50	1627	nM	CHEMBL5432143
5.41	IC50	3900	nM	CHEMBL5172138
5.14	IC50	7200	nM	CHEMBL5173239
5.08	IC50	8400	nM	CHEMBL5185273
5.02	IC50	9560	nM	CHEMBL5411901

PubChem BioAssay actives

3 with measured affinity, of 9 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
2-pyridin-3-ylbenzo[f][1,3]benzoxazole-4,9-dione	1857652: Inhibition of USP36 (unknown origin) using Ub-Rho measured after 0.5 to 3 hrs	ic50	3.9000	uM
2-[6-chloro-2-fluoro-3-[(3R)-1-methylpyrrolidin-3-yl]oxyphenyl]benzo[f][1,3]benzoxazole-4,9-dione	1857652: Inhibition of USP36 (unknown origin) using Ub-Rho measured after 0.5 to 3 hrs	ic50	7.2000	uM
2-[2-chloro-6-fluoro-3-[(3R)-1-methylpyrrolidin-3-yl]oxyphenyl]benzo[f][1,3]benzoxazole-4,9-dione	1857652: Inhibition of USP36 (unknown origin) using Ub-Rho measured after 0.5 to 3 hrs	ic50	8.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cisplatin	decreases expression, increases expression	3
Air Pollutants	increases abundance, increases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Estradiol	increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Cyclosporine	increases expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
geldanamycin	increases expression	1
methylmercuric chloride	increases expression	1
alpha phellandrene	decreases expression	1
deoxynivalenol	increases expression	1
sodium arsenate	increases abundance, increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression, affects cotreatment	1
aflatoxin B2	increases methylation	1
coumarin	increases phosphorylation	1
epigallocatechin gallate	increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
dimethylarsinous acid	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4605988	Binding	Inhibition of human GST-tagged USP36 CD (81 to 461 residues) expressed in Escherichia coli assessed as cleavage of Ubiquitin-Rhodamine110-glycine to Ubiquitin and Rhodamine110-glycine using Ubiquitin-Rhodamine110-glycine as substrate by flu	Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity. — J Med Chem

Clinical trials (associated diseases)

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