USP35

gene
On this page

Also known as KIAA1372

Summary

USP35 (ubiquitin specific peptidase 35, HGNC:20061) is a protein-coding gene on chromosome 11q14.1, encoding Ubiquitin carboxyl-terminal hydrolase 35 (Q9P2H5). Deubiquitinase that plays a role in different processes including cell cycle regulation, mitophagy or endoplasmic reticulum stress.

This gene encodes a member of the peptidase C19 family of ubiquitin-specific proteases. These deubiquitinating enzymes (DUBs) catalyze the removal of ubiquitin proteins from other proteins. The encoded protein associates with polarized mitochondria and has been shown to inhibit NF-kappa B activation and delay PARK2-mediated degradation of mitochondria. Expression of this gene is upregulated by the let-7a microRNA and reduced expression has been observed in human tumor tissues.

Source: NCBI Gene 57558 — RefSeq curated summary.

At a glance

  • GWAS associations: 4
  • Clinical variants (ClinVar): 228 total
  • Druggable target: yes
  • MANE Select transcript: NM_020798

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:20061
Approved symbolUSP35
Nameubiquitin specific peptidase 35
Location11q14.1
Locus typegene with protein product
StatusApproved
AliasesKIAA1372
Ensembl geneENSG00000118369
Ensembl biotypeprotein_coding
OMIM620959
Entrez57558

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000526425, ENST00000528910, ENST00000529308, ENST00000530267, ENST00000530521, ENST00000530535, ENST00000530546, ENST00000869542, ENST00000913725, ENST00000951287

RefSeq mRNA: 1 — MANE Select: NM_020798 NM_020798

CCDS: CCDS41693

Canonical transcript exons

ENST00000529308 — 11 exons

ExonStartEnd
ENSE000011035597819959578199724
ENSE000021497297819623678196918
ENSE000021550347821364678215232
ENSE000021960907818891978189157
ENSE000035195687820753078207623
ENSE000035286607820065078200808
ENSE000035418557820885778208963
ENSE000035941837820013378200234
ENSE000036133927820944878210744
ENSE000036292417820584278206035
ENSE000036599107819793678198068

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 94.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.1191 / max 53.4025, expressed in 1674 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter IDTPM avgSamples expressed
1160153.70431588
1160160.2724111
1160140.142541

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
secondary oocyteCL:000065594.12gold quality
oocyteCL:000002392.09gold quality
pancreatic ductal cellCL:000207991.92silver quality
popliteal arteryUBERON:000225089.54gold quality
tibial arteryUBERON:000761089.53gold quality
right adrenal glandUBERON:000123388.77gold quality
right adrenal gland cortexUBERON:003582788.71gold quality
aortaUBERON:000094788.13gold quality
left adrenal gland cortexUBERON:003582587.69gold quality
left adrenal glandUBERON:000123487.68gold quality
ascending aortaUBERON:000149686.90gold quality
thoracic aortaUBERON:000151586.61gold quality
adrenal cortexUBERON:000123586.24gold quality
endothelial cellCL:000011586.19silver quality
adrenal glandUBERON:000236986.07gold quality
stromal cell of endometriumCL:000225584.91gold quality
right coronary arteryUBERON:000162584.88gold quality
descending thoracic aortaUBERON:000234584.86gold quality
Brodmann (1909) area 23UBERON:001355483.79silver quality
adenohypophysisUBERON:000219683.77gold quality
left coronary arteryUBERON:000162683.72gold quality
middle temporal gyrusUBERON:000277183.49silver quality
pituitary glandUBERON:000000782.99gold quality
coronary arteryUBERON:000162182.55gold quality
right lobe of liverUBERON:000111482.49gold quality
right atrium auricular regionUBERON:000663182.21gold quality
cortical plateUBERON:000534381.82gold quality
cardiac atriumUBERON:000208181.15gold quality
right frontal lobeUBERON:000281080.99gold quality
lower esophagus mucosaUBERON:003583480.85gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

ExperimentMarker?Max mean expression
E-ANND-3no1.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

51 targeting USP35, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-4455100.0065.481587
HSA-MIR-3667-3P99.9967.171636
HSA-MIR-6778-3P99.9667.292693
HSA-MIR-6772-5P99.9467.01577
HSA-MIR-452599.9464.38675
HSA-MIR-5010-5P99.9464.11705
HSA-MIR-651-3P99.9473.485177
HSA-MIR-539-5P99.9370.302855
HSA-MIR-5003-3P99.8569.292517
HSA-MIR-119799.7067.751027
HSA-MIR-6762-3P99.6666.941188
HSA-MIR-561-3P99.6470.903647
HSA-MIR-182799.6368.573265
HSA-MIR-6797-5P99.6166.552084
HSA-MIR-1249-5P99.6166.552049
HSA-MIR-4649-3P99.5666.901783
HSA-MIR-4708-3P99.5167.99870
HSA-MIR-451999.4866.10859
HSA-MIR-6740-3P99.4868.491392
HSA-MIR-94099.3766.142064
HSA-MIR-6808-5P99.3166.232150
HSA-MIR-6893-5P99.3166.252119
HSA-MIR-3614-5P99.3065.25837
HSA-MIR-319999.1765.19696
HSA-MIR-805299.1765.01719
HSA-MIR-7160-5P99.1167.172207
HSA-MIR-6737-3P98.9568.561577
HSA-MIR-7157-3P98.9568.701582
HSA-MIR-6846-5P98.8165.861121
HSA-MIR-6848-5P98.8165.491126

Literature-anchored findings (GeneRIF, showing 13)

  • USP35 does not delay PARK2 recruitment (PMID:25915564)
  • miR let-7a-regulated USP35 can inhibit NF-kappaB activation by deubiquitination and stabilization of ABIN-2 protein (PMID:26348204)
  • findings suggest that USP35 regulates the stability and function of Aurora B by blocking APC(CDH1)-induced proteasomal degradation, thereby controlling mitotic progression (PMID:29449677)
  • Two different USP35 isoforms that localise to different intracellular compartments and have distinct functions. (PMID:29685892)
  • Genome-wide suppressor screen identifies USP35/USP38 as therapeutic candidates for ciliopathies. (PMID:31723061)
  • Deubiquitinase USP35 restrains STING-mediated interferon signaling in ovarian cancer. (PMID:32678307)
  • Deubiquitinase USP35 modulates ferroptosis in lung cancer via targeting ferroportin. (PMID:33931967)
  • USP35, regulated by estrogen and AKT, promotes breast tumorigenesis by stabilizing and enhancing transcriptional activity of estrogen receptor alpha. (PMID:34131114)
  • Regulation of survivin protein stability by USP35 is evolutionarily conserved. (PMID:34438346)
  • USP35 mitigates endoplasmic reticulum stress-induced apoptosis by stabilizing RRBP1 in non-small cell lung cancer. (PMID:34618999)
  • The deubiquitylating enzyme USP35 restricts regulated cell death to promote survival of renal clear cell carcinoma. (PMID:37173391)
  • USP35 promotes hepatocellular carcinoma progression by protecting PKM2 from ubiquitination-mediated degradation. (PMID:37594129)
  • Ubiquitin-specific Protease 35 Promotes Gastric Cancer Metastasis by Increasing the Stability of Snail1. (PMID:38250150)

Cross-species orthologs

2 orthologs

OrganismSymbolGene ID
mus_musculusUsp35ENSMUSG00000035713
rattus_norvegicusUsp35ENSRNOG00000024961

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), 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 35Q9P2H5 (reviewed: Q9P2H5)

Alternative names: Deubiquitinating enzyme 35, Ubiquitin thioesterase 35, Ubiquitin-specific-processing protease 35

All UniProt accessions (4): Q9P2H5, E9PK78, E9PRM2, H0YEP1

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinase that plays a role in different processes including cell cycle regulation, mitophagy or endoplasmic reticulum stress. Inhibits TNFalpha-induced NF-kappa-B activation through stabilizing TNIP2 protein via deubiquitination. Plays an essential role during mitosis by deubiquitinating and thereby regulating the levels of Aurora B/AURKB protein. In addition, regulates the protein levels of other key component of the chromosomal passenger complex (CPC) such as survivin/BIRC5 or Borealin/CDCA8 by enhancing their stability. Regulates the degradation of mitochondria through the process of autophagy termed mitophagy.

Subunit / interactions. Homodimer (via C-terminal region). Interacts with HSP90AA1.

Subcellular location. Cytoplasm. Mitochondrion.

Tissue specificity. Expressed in testis, pancreas and skeletal muscle.

Post-translational modifications. Ubiquitinated by CHIP/STUB1 in an HSP90-dependent manner; leading to proteasomal degradation. This ubiquitination can be reversed through auto-deubiquitinating activity.

Induction. By FOXM1 transcription factor.

Similarity. Belongs to the peptidase C19 family.

Isoforms (2)

UniProt IDNamesCanonical?
Q9P2H5-11yes
Q9P2H5-22

RefSeq proteins (1): NP_065849* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR001394Peptidase_C19_UCHDomain
IPR016024ARM-type_foldHomologous_superfamily
IPR018200USP_CSConserved_site
IPR028889USPDomain
IPR038765Papain-like_cys_pep_sfHomologous_superfamily
IPR049407Usp38-like_NDomain
IPR050164Peptidase_C19Family

Pfam: PF00443, PF21246

UniProt features (49 total): strand 17, helix 10, compositionally biased region 5, region of interest 3, turn 3, active site 2, mutagenesis site 2, sequence conflict 2, chain 1, domain 1, modified residue 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDBMethodResolution (Å)
9F6GX-RAY DIFFRACTION1.5
5TXKX-RAY DIFFRACTION1.84
7Q44X-RAY DIFFRACTION2.2
9F19X-RAY DIFFRACTION2.75

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q9P2H5-F176.560.46

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): 450 (nucleophile); 862 (proton acceptor)

Post-translational modifications (1): 613

Mutagenesis-validated functional residues (2):

PositionPhenotype
450complete loss of catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (3): proteolysis (GO:0006508), protein deubiquitination (GO:0016579), regulation of protein stability (GO:0031647)

GO Molecular Function (4): cysteine-type deubiquitinase activity (GO:0004843), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), mitochondrion (GO:0005739), cytosol (GO:0005829), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
intracellular membrane-bounded organelle2
cytoplasm2
cellular anatomical structure2
protein metabolic process1
cysteine-type deubiquitinase activity1
protein modification by small protein removal1
regulation of biological quality1
cysteine-type peptidase activity1
deubiquitinase activity1
hydrolase activity1
catalytic activity, acting on a protein1
peptidase activity1
catalytic activity1
intracellular anatomical structure1

Protein interactions and networks

STRING

948 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
USP35USP30Q70CQ3761
USP35ZUP1Q96AP4565
USP35USP13Q92995518
USP35USP39Q53GS9517
USP35USP14P54578494
USP35USP53Q70EK8457
USP35USP54Q70EL1454
USP35MARCHF5Q9NX47448
USP35MAVSQ7Z434426
USP35PAN2Q504Q3419
USP35OTUD6AQ7L8S5413
USP35PINK1Q9BXM7413
USP35KCTD21Q4G0X4408
USP35FKBP8Q14318406
USP35USP11P51784404

IntAct

7 interactions, top by confidence:

ABTypeScore
TRIM63USP35psi-mi:“MI:0915”(physical association)0.400
TRIM55USP35psi-mi:“MI:0915”(physical association)0.400
TRIM54USP35psi-mi:“MI:0915”(physical association)0.400
ZNF20ZNF316psi-mi:“MI:0914”(association)0.350
ZNF736PPM1Gpsi-mi:“MI:0914”(association)0.350
FHIP1BMED19psi-mi:“MI:2364”(proximity)0.270

BioGRID (81): USP35 (Affinity Capture-MS), USP35 (Affinity Capture-Western), TMEM173 (Affinity Capture-Western), TNIP2 (Affinity Capture-MS), USP35 (Affinity Capture-Western), USP35 (Reconstituted Complex), AURKB (Affinity Capture-Western), USP35 (Affinity Capture-Western), USP35 (Negative Genetic), MAVS (Affinity Capture-Western), USP35 (Two-hybrid), TMEM173 (Biochemical Activity), USP35 (Affinity Capture-Western), TMEM173 (Affinity Capture-Western), USP35 (Reconstituted Complex)

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

Diamond homologs: A0A0R4IB93, 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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance197
Likely benign7
Benign1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2223 predictions. Top by Δscore:

VariantEffectΔscore
11:78196235:GC:Gacceptor_gain1.0000
11:78197934:A:AGacceptor_gain1.0000
11:78197934:AGAG:Aacceptor_gain1.0000
11:78197935:G:GGacceptor_gain1.0000
11:78197935:GA:Gacceptor_gain1.0000
11:78197935:GAGG:Gacceptor_gain1.0000
11:78197935:GAGGA:Gacceptor_gain1.0000
11:78198064:AGCAG:Adonor_loss1.0000
11:78198065:GCAGG:Gdonor_loss1.0000
11:78198066:CAGGT:Cdonor_loss1.0000
11:78198067:AGGT:Adonor_loss1.0000
11:78198068:GGTGG:Gdonor_loss1.0000
11:78198070:T:Gdonor_loss1.0000
11:78198082:GC:Gdonor_gain1.0000
11:78199621:T:TAacceptor_gain1.0000
11:78199721:GAAG:Gdonor_gain1.0000
11:78199722:AAG:Adonor_loss1.0000
11:78199723:AGG:Adonor_loss1.0000
11:78199725:GTT:Gdonor_loss1.0000
11:78199726:T:Adonor_loss1.0000
11:78200648:A:AGacceptor_gain1.0000
11:78200649:G:GGacceptor_gain1.0000
11:78200671:AT:Aacceptor_gain1.0000
11:78200672:T:TAacceptor_gain1.0000
11:78200684:T:TAacceptor_gain1.0000
11:78200810:T:Gdonor_loss1.0000
11:78205841:G:GTacceptor_gain1.0000
11:78205994:C:Gdonor_gain1.0000
11:78206016:GCCT:Gdonor_gain1.0000
11:78206028:GCGTC:Gdonor_gain1.0000

AlphaMissense

6587 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
11:78196256:T:CI4T1.000
11:78199605:T:AW273R1.000
11:78199605:T:CW273R1.000
11:78199614:T:AW276R1.000
11:78199614:T:CW276R1.000
11:78199641:T:AW285R1.000
11:78199641:T:CW285R1.000
11:78205896:T:AW418R1.000
11:78205896:T:CW418R1.000
11:78205968:G:CG442R1.000
11:78205969:G:AG442D1.000
11:78205972:T:CL443P1.000
11:78205979:C:AN445K1.000
11:78205979:C:GN445K1.000
11:78205992:T:CC450R1.000
11:78205993:G:AC450Y1.000
11:78205994:C:GC450W1.000
11:78206004:A:CS454R1.000
11:78206006:C:AS454R1.000
11:78206006:C:GS454R1.000
11:78208930:A:CD520A1.000
11:78208930:A:TD520V1.000
11:78208945:T:CL525P1.000
11:78208954:T:CL528P1.000
11:78196256:T:AI4N0.999
11:78196256:T:GI4S0.999
11:78196259:T:CL5S0.999
11:78196299:G:CK18N0.999
11:78196299:G:TK18N0.999
11:78198017:T:CL252P0.999

dbSNP variants (sampled 300 via entrez): RS1000063506 (11:78206320 G>C,T), RS1000116380 (11:78202543 A>G), RS1000167572 (11:78229964 G>A,T), RS1000276307 (11:78214864 G>A,C), RS1000309332 (11:78229764 C>A), RS1000316642 (11:78197175 G>T), RS1000338851 (11:78187227 CTT>C), RS1000342286 (11:78230005 A>G,T), RS1000386223 (11:78218666 C>G), RS1000455997 (11:78203680 G>A), RS1000474170 (11:78208775 G>C), RS1000526375 (11:78235217 A>C,G), RS1000613889 (11:78198278 A>G), RS1000628604 (11:78235146 G>C), RS1000680777 (11:78198787 A>C,G)

Disease associations

OMIM: gene MIM:620959 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

StudyTraitp-value
GCST003246_2Testicular germ cell tumor1.000000e-10
GCST007277_15Tourette syndrome5.000000e-06
GCST007656_10Chronic obstructive pulmonary disease or resting heart rate (pleiotropy)4.000000e-12
GCST90013405_23Liver enzyme levels (alanine transaminase)3.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630862 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

ChemicalActions (top 5)PubMed papers
Benzo(a)pyrenedecreases methylation, increases expression2
Valproic Acidaffects expression, decreases methylation2
aristolochic acid Iincreases expression1
FR900359decreases phosphorylation1
bisphenol Aaffects cotreatment, decreases methylation1
arseniteaffects binding, decreases reaction1
tris(1,3-dichloro-2-propyl)phosphateincreases expression1
di-n-butylphosphoric acidaffects expression1
CGP 52608affects binding, increases reaction1
abrinedecreases expression1
jinfukangaffects cotreatment, increases expression1
Sunitinibdecreases expression1
Fulvestrantaffects cotreatment, decreases methylation1
Leflunomidedecreases expression1
Acetaminophendecreases expression1
Air Pollutantsaffects response to substance, increases abundance1
Azathioprineincreases expression1
Cisplatinaffects cotreatment, increases expression1
Nitrogen Oxidesincreases abundance, affects response to substance1
Quercetinincreases expression1
Smokedecreases expression1
Tobacco Smoke Pollutionincreases expression1
Urethaneaffects expression1
Cyclosporineincreases expression1
Copper Sulfateincreases expression1
Particulate Matteraffects response to substance, increases abundance1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL4605987BindingInhibition of USP35 (unknown origin)Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

CellosaurusNameCategorySex
CVCL_TW93HAP1 USP35 (-)Cancer cell lineMale

Clinical trials (associated diseases)

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

  • Disease cohort memberships (association, not causation — diseases whose associated-gene cohort lists this gene; a subset are also under Associated diseases): testicular germ cell tumor