USP33

Summary

USP33 (ubiquitin specific peptidase 33, HGNC:20059) is a protein-coding gene on chromosome 1p31.1, encoding Ubiquitin carboxyl-terminal hydrolase 33 (Q8TEY7). Deubiquitinating enzyme involved in various processes such as centrosome duplication, cellular migration and beta-2 adrenergic receptor/ADRB2 recycling.

This gene encodes a deubiquinating enzyme important in a variety of processes, including Slit-dependent cell migration and beta-2 adrenergic receptor signaling. The protein is negatively regulated through ubiquitination by von Hippel-Lindau tumor protein (VHL). Alternative splicing results in multiple transcript variants and protein isoforms.

Source: NCBI Gene 23032 — RefSeq curated summary.

At a glance

• Gene–disease (curated): renal hypertension (Limited, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 128 total
• Druggable target: yes
• MANE Select transcript: NM_201624

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20059
Approved symbol	USP33
Name	ubiquitin specific peptidase 33
Location	1p31.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1097, VDU1
Ensembl gene	ENSG00000077254
Ensembl biotype	protein_coding
OMIM	615146
Entrez	23032

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 29 protein_coding, 7 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000357428, ENST00000370792, ENST00000370793, ENST00000370794, ENST00000461986, ENST00000462192, ENST00000472462, ENST00000477949, ENST00000481579, ENST00000498328, ENST00000524536, ENST00000524778, ENST00000525113, ENST00000527390, ENST00000528150, ENST00000530709, ENST00000531637, ENST00000533928, ENST00000853330, ENST00000853331, ENST00000853332, ENST00000853333, ENST00000853334, ENST00000853335, ENST00000920219, ENST00000920220, ENST00000920221, ENST00000920222, ENST00000920223, ENST00000955725, ENST00000955726, ENST00000955727, ENST00000955728, ENST00000955729, ENST00000955730, ENST00000955731, ENST00000955732, ENST00000955733, ENST00000955734

RefSeq mRNA: 13 — MANE Select: NM_201624 NM_001377430, NM_001377431, NM_001377432, NM_001377433, NM_001377434, NM_001377435, NM_001377436, NM_001377437, NM_001377438, NM_001377439, NM_015017, NM_201624, NM_201626

CCDS: CCDS678, CCDS679, CCDS680

Canonical transcript exons

ENST00000370794 — 24 exons

Exon	Start	End
ENSE00000775109	77711747	77711855
ENSE00000775111	77714614	77714783
ENSE00000775112	77715742	77715868
ENSE00000775113	77717867	77718047
ENSE00000775127	77728295	77728712
ENSE00000775128	77729860	77729938
ENSE00000775129	77730618	77730731
ENSE00000775130	77734347	77734416
ENSE00000775131	77736056	77736158
ENSE00000775132	77739265	77739417
ENSE00000775133	77740877	77740939
ENSE00001066867	77701369	77701471
ENSE00001123488	77722024	77722196
ENSE00001123496	77723331	77723443
ENSE00001123505	77725622	77725762
ENSE00001215351	77759643	77759852
ENSE00001920503	77695987	77697474
ENSE00003461348	77741617	77741748
ENSE00003569492	77721831	77721925
ENSE00003576600	77721172	77721205
ENSE00003591552	77713200	77713281
ENSE00003613272	77697863	77697931
ENSE00003631989	77741376	77741429
ENSE00003674111	77718596	77718641

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.9810 / max 342.1206, expressed in 1814 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12898	26.0125	1809
12897	6.0557	1618
12899	0.9127	508

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	98.53	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.32	gold quality
pigmented layer of retina	UBERON:0001782	97.45	gold quality
pons	UBERON:0000988	97.39	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.93	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.83	gold quality
parietal pleura	UBERON:0002400	96.80	gold quality
primary visual cortex	UBERON:0002436	96.79	gold quality
endothelial cell	CL:0000115	96.77	gold quality
middle temporal gyrus	UBERON:0002771	96.75	gold quality
cortical plate	UBERON:0005343	96.68	gold quality
superior vestibular nucleus	UBERON:0007227	96.68	gold quality
paraflocculus	UBERON:0005351	96.67	gold quality
occipital lobe	UBERON:0002021	96.64	gold quality
palpebral conjunctiva	UBERON:0001812	96.61	gold quality
parietal lobe	UBERON:0001872	96.51	gold quality
tibia	UBERON:0000979	96.44	gold quality
substantia nigra pars compacta	UBERON:0001965	96.44	gold quality
dorsal root ganglion	UBERON:0000044	96.42	gold quality
pleura	UBERON:0000977	96.42	gold quality
postcentral gyrus	UBERON:0002581	96.33	gold quality
cerebellar cortex	UBERON:0002129	96.32	gold quality
jejunal mucosa	UBERON:0000399	96.28	gold quality
cerebellar hemisphere	UBERON:0002245	96.28	gold quality
seminal vesicle	UBERON:0000998	96.25	gold quality
cerebellum	UBERON:0002037	96.25	gold quality
superior frontal gyrus	UBERON:0002661	96.25	gold quality
lateral globus pallidus	UBERON:0002476	96.23	gold quality
visceral pleura	UBERON:0002401	96.18	gold quality
corpus callosum	UBERON:0002336	96.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6075	no	418.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

115 targeting USP33, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-10527-5P	99.91	72.28	3754

Literature-anchored findings (GeneRIF, showing 27)

• VDU1 has a role in amplifying the increase in type 2 iodothyronine deiodinase activity that results from catecholamine-stimulated de novo synthesis (PMID:12865408)
• The solution structure of the ZnF UBP domain of USP33 has been determined. (PMID:17766394)
• VDU1 was identified as a protein partner of hSP56. (PMID:19118533)
• USP33 and Mdm2 function reciprocally and favor respectively the stability or lability of the receptor beta-arrestin complex (PMID:19363159)
• USPs 20 and 33 serve as novel regulators that dictate both post-endocytic sorting as well as the intensity and extent of beta(2)AR signalling from the cell surface. (PMID:19424180)
• Our results reveal a previously unknown role for USP33 in vertebrate commissural axon guidance and in Slit signaling (PMID:19684588)
• Data uncover a previously unknown function of USP33 and reveal a new player in Slit-Robo signaling in cancer cell migration. (PMID:19706539)
• using human cells, identification of a new mechanism for the regulation of centrosome duplication that requires USP33, a deubiquitinating enzyme that is able to regulate CP110 levels (PMID:23486064)
• nutrient starvation induces RALB deubiquitylation by accumulation and relocalization of the deubiquitylase USP33 to RALB-positive vesicles (PMID:24056301)
• Knockdown or chemical inhibition of p97 causes robust accumulation of USP33 due to inhibition of its degradation (PMID:24855649)
• Data show that ubiquitin specific peptidase 33 (USP33) mediates nerve tissue proteins Slit-Robo signaling in lung cancer cell migration. (PMID:24981056)
• USP33 as a previously unknown tumor-suppressing gene. (PMID:25242263)
• Data show thata combining cyclin-dependent kinase 2 (CDK2) antagonism and ubiquitin thioesterase 33 (USP33) depletion augments anaphase catastrophe via changes in centrosomal protein of 110 kDa (CP110) protein expression. (PMID:26304236)
• USP33 may indirectly regulate the degradation and recycling of CXCR4 through deubiquitinating beta-arrestin2, promoting colorectal tumor cell metastasis. (PMID:27835898)
• the E3 ligase beta-TrCP regulates cellular USP33 levels by the ubiquitin-proteasomal proteolysis. (PMID:28506875)
• Fluorescence-activated cell sorting experiment found no significant effect of USP33 on cell cycle, whereas the apoptotic caspase proteins were activated by USP33-overexpression and the interaction between USP33 and Robo1 protein was identified, and knockdown of Robo1 enhancing the oncogenic effect upon USP33-knockdown, suggesting that USP33 may inhibit tumor progression through Robo1 signaling. (PMID:29533940)
• USP33 was downregulated in gastric adenocarcinoma. (PMID:29802710)
• Our study reveals the inhibitory function of Slit-Robo signalling in gastric cancer (GC) and uncovers a role of USP33 in suppressing cancer cell migration and epithelial-mesenchymal transition by enhancing Slit2-Robo1 signalling. USP33 represents a feasible choice as a prognostic biomarker for GC. (PMID:30896071)
• USP33 deubiquitinates PRKN/parkin and antagonizes its role in mitophagy. (PMID:31432739)
• USP33 regulates c-Met expression by deubiquitinating SP1 to facilitate metastasis in hepatocellular carcinoma. (PMID:32835698)
• Downregulation of USP33 inhibits Slit/Robo signaling pathway and is associated with poor patient survival of glioma. (PMID:32972109)
• Deubiquitinases USP20/33 promote the biogenesis of tail-anchored membrane proteins. (PMID:33792613)
• SARS-CoV-2 Spike Targets USP33-IRF9 Axis via Exosomal miR-148a to Activate Human Microglia. (PMID:33936086)
• Ubiquitin specific peptidase 33 promotes cell proliferation and reduces apoptosis through regulation of the SP1/PI3K/AKT pathway in retinoblastoma. (PMID:34470581)
• USP33 deubiquitinates and stabilizes HIF-2alpha to promote hypoxia response in glioma stem cells. (PMID:35191554)
• USP33 enhances cell survival and stemness by deubiquitinating CTNNB1 in BXPC-3 and SW1990 cells. (PMID:37076992)
• USP33 facilitates the ovarian cancer progression via deubiquitinating and stabilizing CBX2. (PMID:39256572)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp33	ENSDARG00000016163
mus_musculus	Usp33	ENSMUSG00000025437
rattus_norvegicus	Usp33	ENSRNOG00000011294

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), 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 33 — Q8TEY7 (reviewed: Q8TEY7)

Alternative names: Deubiquitinating enzyme 33, Ubiquitin thioesterase 33, Ubiquitin-specific-processing protease 33, VHL-interacting deubiquitinating enzyme 1

All UniProt accessions (6): Q8TEY7, E9PLK7, E9PP47, E9PQP0, H0YCV3, H0YD08

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinating enzyme involved in various processes such as centrosome duplication, cellular migration and beta-2 adrenergic receptor/ADRB2 recycling. Involved in regulation of centrosome duplication by mediating deubiquitination of CCP110 in S and G2/M phase, leading to stabilize CCP110 during the period which centrioles duplicate and elongate. Involved in cell migration via its interaction with intracellular domain of ROBO1, leading to regulate the Slit signaling. Plays a role in commissural axon guidance cross the ventral midline of the neural tube in a Slit-dependent manner, possibly by mediating the deubiquitination of ROBO1. Acts as a regulator of G-protein coupled receptor (GPCR) signaling by mediating the deubiquitination of beta-arrestins (ARRB1 and ARRB2) and beta-2 adrenergic receptor (ADRB2). Plays a central role in ADRB2 recycling and resensitization after prolonged agonist stimulation by constitutively binding ADRB2, mediating deubiquitination of ADRB2 and inhibiting lysosomal trafficking of ADRB2. Upon dissociation, it is probably transferred to the translocated beta-arrestins, leading to beta-arrestins deubiquitination and disengagement from ADRB2. This suggests the existence of a dynamic exchange between the ADRB2 and beta-arrestins. Deubiquitinates DIO2, thereby regulating thyroid hormone regulation. Mediates deubiquitination of both ‘Lys-48’- and ‘Lys-63’-linked polyubiquitin chains.

Subunit / interactions. Interacts with VHL, leading to its ubiquitination and subsequent degradation. Interacts with ARRB1 and ARRB2. Interacts with ADRB2. Interacts with DIO2. Interacts with ROBO1. Interacts with SELENBP1; in a selenium-dependent manner. Interacts with CCP110.

Subcellular location. Cytoplasm. Perinuclear region. Cytoskeleton. Microtubule organizing center. Centrosome Golgi apparatus.

Tissue specificity. Widely expressed.

Post-translational modifications. Ubiquitinated via a VHL-dependent pathway for proteasomal degradation.

Domain organisation. The UBP-type zinc finger binds 3 zinc ions. However, it does not bind ubiquitin, probably because the conserved Arg in position 86 is replaced by a Glu residue.

Similarity. Belongs to the peptidase C19 family. USP20/USP33 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TEY7-1	1	yes
Q8TEY7-2	2
Q8TEY7-3	3

RefSeq proteins (13): NP_001364359, NP_001364360, NP_001364361, NP_001364362, NP_001364363, NP_001364364, NP_001364365, NP_001364366, NP_001364367, NP_001364368, NP_055832, NP_963918, NP_963920 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR001607	Znf_UBP	Domain
IPR006615	Pept_C19_DUSP	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR018200	USP_CS	Conserved_site
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, PF02148, PF06337

UniProt features (47 total): binding site 12, strand 5, splice variant 4, turn 4, domain 3, sequence conflict 3, helix 3, compositionally biased region 3, active site 2, modified residue 2, mutagenesis site 2, region of interest 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2UZG	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TEY7-F1	70.34	0.43

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): 194 (nucleophile); 673 (proton acceptor)

Ligand- & substrate-binding residues (12): 39; 41; 61; 64; 74; 79; 84; 91; 95; 101; 114; 117

Post-translational modifications (2): 377, 439

Mutagenesis-validated functional residues (2):

Position	Phenotype
194	abolishes deubiquitinating activity. does not inhibit lysosomal trafficking of adrb2; when associated with q-673.
673	abolishes deubiquitinating activity. does not inhibit lysosomal trafficking of adrb2; when associated with s-194.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases
R-HSA-9010553	Regulation of expression of SLITs and ROBOs

MSigDB gene sets: 244 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_VACUOLE_ORGANIZATION, GCM_GSPT1, GOBP_POSITIVE_REGULATION_OF_VACUOLE_ORGANIZATION, TTTGTAG_MIR520D, GCM_ZNF198, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_VACUOLE_ORGANIZATION, GOMF_GTPASE_BINDING, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, ACTGCAG_MIR173P, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (13): ubiquitin-dependent protein catabolic process (GO:0006511), endocytosis (GO:0006897), nervous system development (GO:0007399), axon guidance (GO:0007411), regulation of G protein-coupled receptor signaling pathway (GO:0008277), cell migration (GO:0016477), protein deubiquitination (GO:0016579), protein stabilization (GO:0050821), centrosome duplication (GO:0051298), protein K63-linked deubiquitination (GO:0070536), protein K48-linked deubiquitination (GO:0071108), positive regulation of autophagosome assembly (GO:2000786), proteolysis (GO:0006508)

GO Molecular Function (10): G protein-coupled receptor binding (GO:0001664), cysteine-type endopeptidase activity (GO:0004197), cysteine-type deubiquitinase activity (GO:0004843), zinc ion binding (GO:0008270), small GTPase binding (GO:0031267), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (10): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), centrosome (GO:0005813), cytosol (GO:0005829), focal adhesion (GO:0005925), VCB complex (GO:0030891), neuronal cell body (GO:0043025), perinuclear region of cytoplasm (GO:0048471), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Deubiquitination	1
Signaling by ROBO receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
protein deubiquitination	2
cysteine-type peptidase activity	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
system development	1
axonogenesis	1
neuron projection guidance	1
G protein-coupled receptor signaling pathway	1
regulation of signal transduction	1
cell motility	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
regulation of protein stability	1
centrosome cycle	1
cell cycle process	1
autophagosome assembly	1
positive regulation of macroautophagy	1
positive regulation of vacuole organization	1
positive regulation of organelle assembly	1
regulation of autophagosome assembly	1
protein metabolic process	1
signaling receptor binding	1
endopeptidase activity	1
deubiquitinase activity	1
transition metal ion binding	1
GTPase binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1816 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP33	VHL	P40337	919
USP33	CCP110	O43303	738
USP33	WSB1	Q9Y6I7	666
USP33	ZUP1	Q96AP4	612
USP33	USP1	O94782	550
USP33	CCNF	P41002	536
USP33	NEURL4	Q96JN8	520
USP33	ARRB2	P32121	513
USP33	USPL1	Q5W0Q7	508
USP33	USP54	Q70EL1	503
USP33	USP5	P45974	488
USP33	STAMBP	O95630	487
USP33	ZFAND3	Q9H8U3	460
USP33	OTUD7A	Q8TE49	458
USP33	DNAJB4	Q9UDY4	445

IntAct

96 interactions, top by confidence:

A	B	Type	Score
HIF1A	HIF1A	psi-mi:“MI:0915”(physical association)	0.760
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
APBA2	USP33	psi-mi:“MI:0407”(direct interaction)	0.660
APBA2	USP33	psi-mi:“MI:0915”(physical association)	0.660
VAPA	FAM83G	psi-mi:“MI:0914”(association)	0.640
PCGF6	CBX4	psi-mi:“MI:0914”(association)	0.640
VAPA	PITPNM1	psi-mi:“MI:0914”(association)	0.640
HIF1A	USP33	psi-mi:“MI:0915”(physical association)	0.600
USP33	HIF1A	psi-mi:“MI:0407”(direct interaction)	0.600
USP33	ROBO1	psi-mi:“MI:0915”(physical association)	0.560
CT55	BLTP3B	psi-mi:“MI:0914”(association)	0.530
STN1	SMCO3	psi-mi:“MI:0914”(association)	0.530
SPINT2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
LRRTM1	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
SKP2	DPYSL4	psi-mi:“MI:0914”(association)	0.530
TMX1	NRP1	psi-mi:“MI:0914”(association)	0.530
GABRG2	GPAA1	psi-mi:“MI:0914”(association)	0.530

BioGRID (246): USP33 (Biochemical Activity), USP33 (Two-hybrid), USP33 (Affinity Capture-Western), USP33 (Affinity Capture-Western), ARRB2 (Biochemical Activity), USP33 (Affinity Capture-MS), USP33 (Affinity Capture-MS), USP33 (Affinity Capture-MS), USP33 (Affinity Capture-MS), USP33 (Affinity Capture-MS), USP33 (Affinity Capture-MS), USP33 (Affinity Capture-MS), USP33 (Affinity Capture-MS), USP33 (Affinity Capture-MS), USP33 (Synthetic Lethality)

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

2 interactions.

A	Effect	B	Mechanism
VCB-Cul2	“down-regulates quantity by destabilization”	USP33	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 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
GRB2 events in EGFR signaling	5	53.6×	1e-05
SHC1 events in EGFR signaling	5	50.3×	1e-05
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	40.2×	2e-05
Cargo recognition for clathrin-mediated endocytosis	5	7.4×	6e-03
Clathrin-mediated endocytosis	6	7.2×	3e-03
Ub-specific processing proteases	8	6.0×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	90
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3591 predictions. Top by Δscore:

Variant	Effect	Δscore
1:77697857:ACTT:A	donor_loss	1.0000
1:77697858:CTTA:C	donor_loss	1.0000
1:77697859:TTA:T	donor_loss	1.0000
1:77697860:TACCT:T	donor_loss	1.0000
1:77697861:A:T	donor_loss	1.0000
1:77697862:C:CG	donor_loss	1.0000
1:77697932:C:CC	acceptor_gain	1.0000
1:77711777:T:TA	donor_gain	1.0000
1:77711854:ACC:A	acceptor_loss	1.0000
1:77711856:C:CA	acceptor_loss	1.0000
1:77711857:T:C	acceptor_loss	1.0000
1:77713195:CAAA:C	donor_loss	1.0000
1:77713196:AAACC:A	donor_loss	1.0000
1:77713197:AACCT:A	donor_loss	1.0000
1:77713198:ACCTG:A	donor_loss	1.0000
1:77713199:CCTGC:C	donor_loss	1.0000
1:77713279:CAC:C	acceptor_gain	1.0000
1:77713282:C:CA	acceptor_loss	1.0000
1:77717863:TTACT:T	donor_loss	1.0000
1:77717864:TACTA:T	donor_loss	1.0000
1:77717865:A:AC	donor_gain	1.0000
1:77717865:ACTAC:A	donor_loss	1.0000
1:77717866:C:CC	donor_gain	1.0000
1:77717866:CT:C	donor_gain	1.0000
1:77717866:CTA:C	donor_gain	1.0000
1:77717866:CTACT:C	donor_gain	1.0000
1:77718048:C:CC	acceptor_gain	1.0000
1:77718590:CCATA:C	donor_loss	1.0000
1:77718593:TAC:T	donor_loss	1.0000
1:77718594:A:T	donor_loss	1.0000

AlphaMissense

6057 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:77701397:C:A	W858C	1.000
1:77701397:C:G	W858C	1.000
1:77701399:A:G	W858R	1.000
1:77701399:A:T	W858R	1.000
1:77701411:A:G	W854R	1.000
1:77701411:A:T	W854R	1.000
1:77711816:A:C	C810W	1.000
1:77711817:C:T	C810Y	1.000
1:77711818:A:G	C810R	1.000
1:77713217:C:A	W791C	1.000
1:77713217:C:G	W791C	1.000
1:77713219:A:G	W791R	1.000
1:77713219:A:T	W791R	1.000
1:77714624:A:C	C766W	1.000
1:77714626:A:G	C766R	1.000
1:77714686:A:G	W746R	1.000
1:77714686:A:T	W746R	1.000
1:77714702:A:C	F740L	1.000
1:77714702:A:T	F740L	1.000
1:77714704:A:G	F740L	1.000
1:77715751:A:G	L710P	1.000
1:77715799:A:T	V694D	1.000
1:77715808:T:A	D691V	1.000
1:77715824:A:G	W686R	1.000
1:77715824:A:T	W686R	1.000
1:77715860:A:G	Y674H	1.000
1:77715861:G:C	H673Q	1.000
1:77715861:G:T	H673Q	1.000
1:77715863:G:C	H673D	1.000
1:77715865:C:A	G672V	1.000

dbSNP variants (sampled 300 via entrez): RS1000066820 (1:77706653 C>G), RS1000110592 (1:77731631 C>T), RS1000186849 (1:77702438 C>T), RS1000231157 (1:77753888 A>G), RS1000233326 (1:77761151 G>A,C,T), RS1000252312 (1:77754546 T>C), RS1000296922 (1:77708585 A>G), RS1000352269 (1:77717515 A>G), RS1000356555 (1:77724578 T>C), RS1000367275 (1:77759992 T>A,G), RS1000385685 (1:77722452 C>T), RS1000443747 (1:77715559 T>G), RS1000449608 (1:77737491 G>A), RS1000456237 (1:77703770 C>T), RS1000468742 (1:77717186 T>A)

Disease associations

OMIM: gene MIM:615146 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
renal hypertension	Limited	Autosomal dominant

Mondo (1): renal hypertension (MONDO:0001105)

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003262_355	Post bronchodilator FEV1	4.000000e-06
GCST010988_240	Adult body size	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006977	Hypertension, Renal	C12.050.351.968.419.331; C12.200.777.419.331; C12.950.419.331; C14.907.489.631

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291551 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	4
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	affects binding, decreases reaction	1
beta-methylcholine	affects expression	1
CGP 52608	increases reaction, affects binding	1
corosolic acid	increases expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Dexamethasone	affects cotreatment, increases expression	1
Gold	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Hydrogen Peroxide	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Selenium	affects cotreatment, decreases expression	1
Vitamin E	affects cotreatment, decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin M1	decreases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5228941	Binding	Binding affinity to biotinylated USP33 zinc finger ubiquitin binding domain (29 to 134 residues) (unknown origin) expressed in Escherichia coli incubated for 120 secs by Biolayer Interferometry assay	Structure-Activity Relationship of USP5 Inhibitors. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3L1	Abcam HEK293T USP33 KO	Transformed cell line	Female
CVCL_TW90	HAP1 USP33 (-) 1	Cancer cell line	Male
CVCL_TW91	HAP1 USP33 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01840540	PHASE1	COMPLETED	MSC for Occlusive Disease of the Kidney
NCT00868972	PHASE2/PHASE3	UNKNOWN	Renal Stenting With Distal Atheroembolic Protection
NCT00006173	Not specified	COMPLETED	Magnetic Resonance Imaging for Evaluating Kidney Function
NCT01766427	Not specified	COMPLETED	Electroacupuncture for Hypertension Patients With Chronic Kidney Disease
NCT05834803	Not specified	RECRUITING	Effects of Percutaneous Transluminal Renal Angioplasty of Atherosclerotic Renal Artery Stenosis in High-Risk Patients.
NCT07531966	Not specified	RECRUITING	Vascular Complications After Kidney Transplantation