UCHL3

Summary

UCHL3 (ubiquitin C-terminal hydrolase L3, HGNC:12515) is a protein-coding gene on chromosome 13q22.2, encoding Ubiquitin carboxyl-terminal hydrolase isozyme L3 (P15374). Deubiquitinating enzyme (DUB) that controls levels of cellular ubiquitin through processing of ubiquitin precursors and ubiquitinated proteins.

The protein encoded by this gene is a member of the deubiquitinating enzyme family. Members of this family are proteases that catalyze the removal of ubiquitin from polypeptides and are divided into five classes, depending on the mechanism of catalysis. This protein may hydrolyze the ubiquitinyl-N-epsilon amide bond of ubiquitinated proteins to regenerate ubiquitin for another catalytic cycle. Alternative splicing results in multiple transcript variants that encode different protein isoforms.

Source: NCBI Gene 7347 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 32 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_006002

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12515
Approved symbol	UCHL3
Name	ubiquitin C-terminal hydrolase L3
Location	13q22.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000118939
Ensembl biotype	protein_coding
OMIM	603090
Entrez	7347

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000377595, ENST00000419068, ENST00000471792, ENST00000606347, ENST00000607339, ENST00000869068, ENST00000963591, ENST00000963592, ENST00000963593

RefSeq mRNA: 2 — MANE Select: NM_006002 NM_001270952, NM_006002

CCDS: CCDS9453

Canonical transcript exons

ENST00000377595 — 9 exons

Exon	Start	End
ENSE00000684192	75604769	75604827
ENSE00002702355	75549791	75549862
ENSE00003470896	75549976	75549987
ENSE00003480463	75569460	75569507
ENSE00003490462	75566695	75566851
ENSE00003553290	75567227	75567312
ENSE00003599610	75560753	75560881
ENSE00003689061	75594915	75594990
ENSE00003749069	75605729	75606020

Expression profiles

Bgee: expression breadth ubiquitous, 152 present calls, max score 95.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.3701 / max 531.8351, expressed in 1814 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
135397	35.6093	1812
135395	3.6297	1425
135396	1.1311	756

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	95.95	gold quality
right adrenal gland cortex	UBERON:0035827	95.83	gold quality
left adrenal gland	UBERON:0001234	95.52	gold quality
islet of Langerhans	UBERON:0000006	95.34	gold quality
left adrenal gland cortex	UBERON:0035825	95.25	gold quality
adrenal gland	UBERON:0002369	95.21	gold quality
esophagus mucosa	UBERON:0002469	95.02	gold quality
rectum	UBERON:0001052	94.89	gold quality
adrenal tissue	UBERON:0018303	94.46	gold quality
lower esophagus mucosa	UBERON:0035834	94.33	gold quality
skin of leg	UBERON:0001511	93.73	gold quality
zone of skin	UBERON:0000014	93.68	gold quality
gastrocnemius	UBERON:0001388	93.68	gold quality
skin of abdomen	UBERON:0001416	93.58	gold quality
muscle of leg	UBERON:0001383	93.37	gold quality
pancreas	UBERON:0001264	93.29	gold quality
mucosa of transverse colon	UBERON:0004991	93.15	gold quality
left testis	UBERON:0004533	92.94	gold quality
body of pancreas	UBERON:0001150	92.90	gold quality
tonsil	UBERON:0002372	92.86	gold quality
right testis	UBERON:0004534	92.77	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.71	gold quality
left lobe of thyroid gland	UBERON:0001120	92.69	gold quality
testis	UBERON:0000473	92.68	gold quality
thyroid gland	UBERON:0002046	92.60	gold quality
placenta	UBERON:0001987	92.29	gold quality
right lobe of thyroid gland	UBERON:0001119	92.20	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.05	gold quality
amygdala	UBERON:0001876	91.73	gold quality
smooth muscle tissue	UBERON:0001135	91.65	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.35
E-MTAB-7606	no	331.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1

miRNA regulators (miRDB)

26 targeting UCHL3, 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-5692A	100.00	74.40	6850
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-5590-3P	99.48	70.91	2429
HSA-MIR-142-5P	99.48	70.92	2416
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4684-3P	98.24	69.91	1075
HSA-MIR-490-3P	97.79	65.54	606
HSA-MIR-8055	97.62	66.09	1023
HSA-MIR-500A-3P	97.60	67.48	595
HSA-MIR-6750-3P	96.79	67.50	740
HSA-MIR-8081	96.42	67.75	738

Literature-anchored findings (GeneRIF, showing 33)

• 1.45 A resolution crystal structure of human UCH-L3 in complex with the inhibitor ubiquitin vinylmethylester, an inhibitor that forms a covalent adduct with the active site cysteine of ubiquitin-specific proteases (PMID:15531586)
• Upregulation of UCH-L3 is associated with Uterine Cervical Neoplasms (PMID:16402389)
• Substrate filtering by the active site crossover loop in UCHL3 revealed by sortagging and gain-of-function mutations. (PMID:19047059)
• These results indicate that mono-Ub and Ub dimers may regulate the enzymatic functions of UCH-L1 and UCH-L3, respectively, in vivo. (PMID:19154770)
• Untangling the folding mechanism of the 5(2)-knotted protein UCH-L3 (PMID:19476499)
• identification and the sequence-specific assignments for 186 out of the 218 UCH-L3 (230 less 12 prolines) backbone 15N and amide proton resonances (PMID:19636824)
• impaired UCH-L3 function may contribute to the accumulation of full length UBB(+1) in various pathologie (PMID:21762696)
• Data identified of UCHL3 as an essential deubiquitinase in adipogenesis. (PMID:22679485)
• UCH-L3 is a novel regulator of epithelial-mesenchymal transition and cell migration in prostate cancer cells. (PMID:25194810)
• Using a series of engineered protein substrates, which are similar in size yet differ in secondary structure, we demonstrate that thermal stability is a key factor that significantly affects UCH-L3 hydrolysis. (PMID:25369561)
• Study demonstrated positive correlations between the level and activity of UCHL3 and sperm characteristics and function suggesting that UCHL3 may play a role in male infertility. (PMID:27780264)
• The authors find that UCHL3 regulates COPS5-dependent deneddylation of Cullin1, which is an essential component of SCF(beta-TrCP) complex and associated with SCF(beta-TrCP) activities. The authors further demonstrate that UCHL3 upregulates the levels of SCF(beta-TrCP) substrates including IFN-I receptor IFNAR1, which enhances IFN-I mediated signaling pathway and antiviral activity. (PMID:28583475)
• Depletion of UCHL3 increases TDP1 ubiquitylation and turnover rate and sensitizes cells to TOP1 poisons. Overexpression of UCHL3, but not a catalytically inactive mutant, suppresses TDP1 ubiquitylation and turnover rate. (PMID:29898404)
• UCHL3 facilitates cellular viability after DSB induction by antagonizing Ku80 ubiquitylation to enhance Ku80 retention at sites of damage. (PMID:30559450)
• Our results indicate that highly expressed UCHL3 enhances inflammation by stabilizing TRAF2, which in turn facilitates tumourigenesis in ovarian cancer, and that UCHL3 is a potential target for ovarian cancer patients with increased inflammation. (PMID:31477831)
• UCH-L3 might play a role in epithelial ovarian cancer pathogenesis and progression (PMID:31642235)
• UCH-L3 promotes non-small cell lung cancer proliferation via accelerating cell cycle and inhibiting cell apoptosis. (PMID:32180254)
• Ubiquitin Carboxyl-Terminal Hydrolases (UCHs): Potential Mediators for Cancer and Neurodegeneration. (PMID:32486284)
• The deubiquitylase UCHL3 maintains cancer stem-like properties by stabilizing the aryl hydrocarbon receptor. (PMID:32546741)
• Deubiquitylase UCHL3 regulates bi-orientation and segregation of chromosomes during mitosis. (PMID:32738097)
• K27-Linked Diubiquitin Inhibits UCHL3 via an Unusual Kinetic Trap. (PMID:33238157)
• UCHL3 promotes aerobic glycolysis of pancreatic cancer through upregulating LDHA expression. (PMID:33616859)
• Silencing UCHL3 enhances radio-sensitivity of non-small cell lung cancer cells by inhibiting DNA repair. (PMID:34016790)
• Rational Development and Characterization of a Ubiquitin Variant with Selectivity for Ubiquitin C-Terminal Hydrolase L3. (PMID:35053210)
• Knockdown of UCHL3 inhibits esophageal squamous cell carcinoma progression by reducing CRY2 methylation. (PMID:35088238)
• The deubiquitinase UCHL3 mediates p300-dependent chemokine signaling in alveolar type II cells to promote pulmonary fibrosis. (PMID:37524875)
• Activation of CTNNB1 by deubiquitinase UCHL3-mediated stabilization facilitates bladder cancer progression. (PMID:37740194)
• UCHL3 inhibits ferroptosis by stabilizing beta-catenin and maintains stem-like properties of hepatocellular carcinoma cells. (PMID:38092274)
• UCHL-3 as a potential biomarker of ovarian cancer. (PMID:38266402)
• CircMTA2 Drives Gastric Cancer Progression through Suppressing MTA2 Degradation via Interacting with UCHL3. (PMID:38474064)
• GSK3beta and UCHL3 govern RIPK4 homeostasis via deubiquitination to enhance tumor metastasis in ovarian cancer. (PMID:38664501)
• UCHL3 promotes hepatocellular carcinoma progression by stabilizing EEF1A1 through deubiquitination. (PMID:38965582)
• Role of UCHL3 in health and disease. (PMID:39226739)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	uchl3	ENSDARG00000030177
mus_musculus	Uchl3	ENSMUSG00000022111
mus_musculus	Uchl4	ENSMUSG00000035337
rattus_norvegicus	Uchl3	ENSRNOG00000009530
rattus_norvegicus	Uchl3	ENSRNOG00000065893
rattus_norvegicus		ENSRNOG00000070918
caenorhabditis_elegans		WBGENE00006721
caenorhabditis_elegans		WBGENE00006722
caenorhabditis_elegans		WBGENE00006723

Paralogs (3): UCHL5 (ENSG00000116750), UCHL1 (ENSG00000154277), BAP1 (ENSG00000163930)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase isozyme L3 — P15374 (reviewed: P15374)

Alternative names: Ubiquitin thioesterase L3

All UniProt accessions (3): P15374, A0A140VJZ4, Q5TBK7

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinating enzyme (DUB) that controls levels of cellular ubiquitin through processing of ubiquitin precursors and ubiquitinated proteins. Thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of either ubiquitin or NEDD8. Has a 10-fold preference for Arg and Lys at position P3’’, and exhibits a preference towards ‘Lys-48’-linked ubiquitin chains. Deubiquitinates ENAC in apical compartments, thereby regulating apical membrane recycling. Indirectly increases the phosphorylation of IGFIR, AKT and FOXO1 and promotes insulin-signaling and insulin-induced adipogenesis. Required for stress-response retinal, skeletal muscle and germ cell maintenance. May be involved in working memory. Can hydrolyze UBB(+1), a mutated form of ubiquitin which is not effectively degraded by the proteasome and is associated with neurodegenerative disorders.

Subunit / interactions. Preferentially binds diubiquitin; the interaction does not hydrolyze diubiquitin but, in vitro, inhibits the hydrolyzing activity on other substrates.

Subcellular location. Cytoplasm.

Tissue specificity. Highly expressed in heart, skeletal muscle, and testis.

Activity regulation. Inhibited by monoubiquitin and diubiquitin.

Miscellaneous. Identified as a tumor-specific antigen in colon cancer.

Similarity. Belongs to the peptidase C12 family.

RefSeq proteins (2): NP_001257881, NP_005993* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001578	Peptidase_C12_UCH	Domain
IPR036959	Peptidase_C12_UCH_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR057254	UCH_AS	Conserved_site

Pfam: PF01088

Enzyme classification (BRENDA):

• EC 3.4.19.12 — ubiquitinyl hydrolase 1 (BRENDA: 30 organisms, 328 substrates, 173 inhibitors, 70 Km, 58 kcat entries)

Substrate kinetics (BRENDA)

29 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
UBIQUITIN-7-AMIDO-4-METHYLCOUMARIN	—	7
DABCYL-FKKKGGGDVKE-EDANS	0.0142–0.0616	6
UBIQUITIN 7-AMIDO-4-METHYLCOUMARIN	—	5
UBIQUITIN ETHYL ESTER	0.0006–0.03	5
DABCYL-FRLKGGAPIKGV-EDANS	0.0048–0.0217	3
UBIQUITIN-W-G75A	0.0001–0.0004	2
UBIQUITIN-W-G76A	0.0011–0.002	2
UBIQUITIN-W-H68A	0.0005	2
UBIQUITIN-W-I44A	0.0003–0.0004	2
UBIQUITIN-W-K11A	0.0011–0.0023	2
UBIQUITIN-W-K48A	0.0003–0.0007	2
UBIQUITIN-W-K63A	0.0004–0.0008	2
UBIQUITIN-W-K6A	0.0009–0.0014	2
UBIQUITIN-W-L71A	0.008–0.0198	2
UBIQUITIN-W-L73A	0.0058–0.0104	2

UniProt features (33 total): helix 10, strand 9, mutagenesis site 3, region of interest 3, active site 2, site 2, chain 1, domain 1, turn 1, modified residue 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
1XD3	X-RAY DIFFRACTION	1.45
7YV4	X-RAY DIFFRACTION	1.58
1UCH	X-RAY DIFFRACTION	1.8
6ISU	X-RAY DIFFRACTION	1.87
6QML	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15374-F1	94.85	0.89

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 (4): 95 (nucleophile); 169 (proton donor); 89 (transition state stabilizer); 184 (important for enzyme activity)

Post-translational modifications (1): 130

Mutagenesis-validated functional residues (3):

Position	Phenotype
33	decreased interaction with diubiquitin. no accumulation of free diubiquitin. decreased levels of polyubiquitinated lysoz
95	increased interaction with diubiquitin.
95	abolishes enzymatic activity. increased interaction with diubiquitin.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5689603	UCH proteinases
R-HSA-8866652	Synthesis of active ubiquitin: roles of E1 and E2 enzymes
R-HSA-8951664	Neddylation

MSigDB gene sets: 168 (showing top): RNGTGGGC_UNKNOWN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, WONG_PROTEASOME_GENE_MODULE, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, PUJANA_CHEK2_PCC_NETWORK, WEI_MYCN_TARGETS_WITH_E_BOX, SCHUHMACHER_MYC_TARGETS_UP, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, WTGAAAT_UNKNOWN, ZIC1_01, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, ACTTTAT_MIR1425P, EGR1_01, VANTVEER_BREAST_CANCER_ESR1_DN, FOXJ2_02

GO Biological Process (6): ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), protein deubiquitination (GO:0016579), protein catabolic process (GO:0030163), post-translational protein modification (GO:0043687), proteolysis (GO:0006508)

GO Molecular Function (8): cysteine-type deubiquitinase activity (GO:0004843), peptidase activity (GO:0008233), deNEDDylase activity (GO:0019784), ubiquitin binding (GO:0043130), protein binding (GO:0005515), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), deubiquitinase activity (GO:0101005)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Deubiquitination	1
Protein ubiquitination	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein metabolic process	2
ubiquitin-like protein peptidase activity	2
cytoplasm	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
macromolecule catabolic process	1
protein modification process	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
ubiquitin-like protein binding	1
binding	1
peptidase activity	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1998 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UCHL3	ZUP1	Q96AP4	858
UCHL3	LMO7	Q8WWI1	856
UCHL3	JOSD2	Q8TAC2	829
UCHL3	JOSD1	Q15040	821
UCHL3	COMMD6	Q7Z4G1	821
UCHL3	UBB	P02248	812
UCHL3	USP5	P45974	769
UCHL3	USP14	P54578	761
UCHL3	USP1	O94782	757
UCHL3	SENP8	Q96LD8	716
UCHL3	ATXN3	P54252	710
UCHL3	USP2	O75604	708
UCHL3	USP7	Q93009	690
UCHL3	USP15	Q9Y4E8	659
UCHL3	NEDD8	Q15843	658

IntAct

39 interactions, top by confidence:

A	B	Type	Score
UCHL3	CLPB	psi-mi:“MI:0915”(physical association)	0.640
DMWD	UCHL3	psi-mi:“MI:0915”(physical association)	0.560
UCHL3	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
UCHL3	ZMYM6	psi-mi:“MI:0914”(association)	0.530
UCHL3	UBB	psi-mi:“MI:0407”(direct interaction)	0.440
SMAD1	UCHL3	psi-mi:“MI:0915”(physical association)	0.400
Smad1	UCHL3	psi-mi:“MI:0915”(physical association)	0.400
NSG2	UCHL3	psi-mi:“MI:0915”(physical association)	0.370
UCHL3	POGK	psi-mi:“MI:0915”(physical association)	0.370
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
COPS5		psi-mi:“MI:0914”(association)	0.350
COPS6		psi-mi:“MI:0914”(association)	0.350
USP20		psi-mi:“MI:0914”(association)	0.350
ARHGAP35	CSTB	psi-mi:“MI:0914”(association)	0.350
Arhgap18	KRT86	psi-mi:“MI:0914”(association)	0.350
ARHGAP11B	RPN1	psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CPNE2	SUPT5H	psi-mi:“MI:0914”(association)	0.350
CST5	UCHL3	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (254): PLA2G2A (Biochemical Activity), UBC (Reconstituted Complex), NEDD8 (Biochemical Activity), UCHL3 (Reconstituted Complex), UCHL3 (Reconstituted Complex), CLPB (Affinity Capture-MS), ZMYM6 (Affinity Capture-MS), UBC (Biochemical Activity), ACAA2 (Co-fractionation), ARHGDIA (Co-fractionation), GDI1 (Co-fractionation), GPX4 (Co-fractionation), HINT1 (Co-fractionation), IMPDH2 (Co-fractionation), MAPRE1 (Co-fractionation)

ESM2 similar proteins: A0FKG7, A1YER2, A1YFX9, A2T7G9, B0BN93, O04482, O80526, O88600, P09936, P15374, P21343, P23356, P50103, P54577, P84169, P87362, Q00981, Q06AB3, Q06AT3, Q28DS0, Q29465, Q2QNG7, Q2QZ86, Q2TBG8, Q4KM49, Q5E964, Q5E982, Q5F3A6, Q5R5C9, Q5R8T5, Q5RDM4, Q5ZJ08, Q60HC8, Q61316, Q6SEG5, Q8GWE1, Q8JGT5, Q91WQ3, Q91Y78, Q9BUP3

Diamond homologs: O01391, P09936, P15374, P23356, P35122, P35127, P50103, P58321, Q00981, Q06AB3, Q10171, Q2TBG8, Q54T48, Q60HC8, Q6SEG5, Q8GWE1, Q8IKM8, Q91Y78, Q9GM50, Q9JKB1, Q9R0P9, Q9WUP7, Q9FFF2, O04482, Q9UUB6, B3NPV7, B4GAM2, B4HST0, B4P6P6, B4QHH0, Q291J4, Q7K5N4, A1L2G3, A2VDM8, B0W2R4, B3MIV9, B4JW98, B4KT51, B4LQ24, C4A0D9

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
UCHL3	“up-regulates quantity”	UBA52	cleavage
UCHL3	“up-regulates quantity”	RPS27A	cleavage
UCHL3	“up-regulates quantity”	Ubiquitin	cleavage
ATM	“up-regulates activity”	UCHL3	phosphorylation
UCHL3	“up-regulates activity”	RAD51	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 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
Ub-specific processing proteases	6	14.5×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1432 predictions. Top by Δscore:

Variant	Effect	Δscore
13:75560752:GTTT:G	acceptor_gain	1.0000
13:75566691:A:G	acceptor_gain	1.0000
13:75566693:A:AG	acceptor_gain	1.0000
13:75566694:G:GT	acceptor_gain	1.0000
13:75566694:GT:G	acceptor_gain	1.0000
13:75566694:GTAT:G	acceptor_gain	1.0000
13:75566848:TTTGG:T	donor_loss	1.0000
13:75566850:TGGTA:T	donor_loss	1.0000
13:75566852:G:GG	donor_gain	1.0000
13:75566853:T:G	donor_loss	1.0000
13:75567217:A:AG	acceptor_gain	1.0000
13:75567218:T:G	acceptor_gain	1.0000
13:75567219:A:AG	acceptor_gain	1.0000
13:75567220:T:G	acceptor_gain	1.0000
13:75567224:CAGA:C	acceptor_loss	1.0000
13:75567225:A:AG	acceptor_gain	1.0000
13:75567225:AGAA:A	acceptor_loss	1.0000
13:75567226:G:GG	acceptor_gain	1.0000
13:75567226:GA:G	acceptor_gain	1.0000
13:75567226:GAA:G	acceptor_gain	1.0000
13:75567226:GAAT:G	acceptor_gain	1.0000
13:75567226:GAATC:G	acceptor_gain	1.0000
13:75567310:GAT:G	donor_gain	1.0000
13:75567313:G:GG	donor_gain	1.0000
13:75569454:TTACA:T	acceptor_loss	1.0000
13:75569455:TACAG:T	acceptor_loss	1.0000
13:75569456:ACAGG:A	acceptor_loss	1.0000
13:75569457:CAG:C	acceptor_loss	1.0000
13:75569458:A:AC	acceptor_loss	1.0000
13:75569459:G:GT	acceptor_loss	1.0000

AlphaMissense

1522 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:75594948:T:C	F170L	1.000
13:75594950:T:A	F170L	1.000
13:75594950:T:G	F170L	1.000
13:75605783:T:C	F222L	1.000
13:75605785:T:A	F222L	1.000
13:75605785:T:G	F222L	1.000
13:75549836:T:A	W6R	0.999
13:75549836:T:C	W6R	0.999
13:75560849:G:C	A51P	0.999
13:75560850:C:A	A51E	0.999
13:75560864:T:C	F56L	0.999
13:75560866:T:A	F56L	0.999
13:75560866:T:G	F56L	0.999
13:75566778:A:C	Q89H	0.999
13:75566778:A:T	Q89H	0.999
13:75566794:T:C	C95R	0.999
13:75566795:G:A	C95Y	0.999
13:75566798:G:A	G96E	0.999
13:75566798:G:T	G96V	0.999
13:75566807:G:A	G99E	0.999
13:75569488:C:A	A152D	0.999
13:75594945:C:G	H169D	0.999
13:75594947:T:A	H169Q	0.999
13:75594947:T:G	H169Q	0.999
13:75604771:G:A	G185R	0.999
13:75604771:G:C	G185R	0.999
13:75604771:G:T	G185W	0.999
13:75604772:G:A	G185E	0.999
13:75604772:G:T	G185V	0.999
13:75605784:T:C	F222S	0.999

dbSNP variants (sampled 300 via entrez): RS1000103111 (13:75548287 A>G), RS1000119271 (13:75603793 G>T), RS1000164377 (13:75580474 A>G), RS1000222821 (13:75561791 A>G), RS1000247791 (13:75569170 A>G), RS1000343889 (13:75573955 C>T), RS1000344656 (13:75555459 C>T), RS1000397529 (13:75573766 C>T), RS1000442089 (13:75562115 A>G), RS1000542904 (13:75593093 A>C,G,T), RS1000559485 (13:75563280 A>G), RS1000624413 (13:75557086 A>G), RS1000638999 (13:75602205 G>A), RS1000750960 (13:75561118 A>G), RS1000758946 (13:75605391 C>T)

Disease associations

OMIM: gene MIM:603090 | 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
GCST001977_1	Diabetic retinopathy	7.000000e-06
GCST009391_39	Metabolite levels	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010116	choline measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6195 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 36,161 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL590	MENADIONE	4	21,034
CHEMBL372764	PERIFOSINE	3	15,127

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C12: Ubiquitin C-terminal hydrolase

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 6 [PMID: 17948018]	Inhibition	6.22	pIC50

Binding affinities (BindingDB)

5 measured of 16 human assays (17 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
ML323	IC50	17 nM	US-9802904: Inhibitors of the USP1/UAF1 deubiquitinase complex and uses thereof
5-Chloro-1-[(2,5-dichlorophenyl)methyl]-1H-indole-2,3-dione 3-(O-acetyloxime)	IC50	2500 nM
Acetyl Isogambogic Acid	IC50	11100 nM
Mangiferin	IC50	56600 nM
5-(4-fluorophenyl)-3-hydroxy-4-[(5-methylfuran-2-yl)carbonyl]-1-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrrol-2-one	IC50	123000 nM

ChEMBL bioactivities

6 potent at pChembl≥5 of 17 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.30	IC50	50	nM	PERIFOSINE
6.22	IC50	600	nM	CHEMBL1241028
5.67	IC50	2160	nM	CHEMBL3407501
5.30	IC50	5000	nM	CHEMBL5193983
5.00	IC50	1e+04	nM	CHEMBL1397260

PubChem BioAssay actives

6 with measured affinity, of 75 total; 5 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
(1,1-dimethylpiperidin-1-ium-4-yl) octadecyl phosphate	1871610: Inhibition of UCHL3 (unknown origin) assessed as reduction in RAD51 deubiquitination incubated for 4 hrs	ic50	0.0500	uM
4,5,6,7-tetrachloroindene-1,3-dione	1871604: Inhibition of recombinant human UCHL3 expressed in baculovirus infected Sf9 cells using ubiquitin-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence spectrophotometric assay	ic50	0.6000	uM
2-(4-fluorophenyl)benzo[f][1,3]benzoxazole-4,9-dione	1871603: Inhibition of UCHL3 (unknown origin) using ubiquitin-AMC as substrate by fluorescence assay	ic50	2.1600	uM
methyl 5-amino-6-(7-amino-6-methoxy-5,8-dioxoquinolin-2-yl)-4-(2-hydroxy-3,4-dimethoxyphenyl)pyridine-2-carboxylate	1871602: Inhibition of UCHL3 (unknown origin) incubated for 20 mins by fluorescence assay	ic50	5.0000	uM
(Z)-7-[(1S,5R)-5-[(E,3S)-3-hydroxyoct-1-enyl]-4-oxocyclopent-2-en-1-yl]hept-5-enoic acid	1871601: Inhibition of UCHL3 (unknown origin) using Ub-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	9
trichostatin A	affects cotreatment, increases expression	3
cobaltous chloride	decreases expression	3
bisphenol S	affects cotreatment, increases methylation, decreases expression, increases expression	3
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	increases expression	2
GSK-J4	increases expression	1
dicrotophos	decreases expression	1
bisphenol A	affects expression	1
senecionine	increases expression	1
senkirkine	increases expression	1
titanium dioxide	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Benztropine	decreases expression	1
Cannabidiol	affects cotreatment, decreases expression	1
Cuprizone	decreases expression, affects cotreatment	1

ChEMBL screening assays

36 unique, capped per target: 36 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1243700	Binding	Inhibition of UCHL3 in human H1299 cells	Mechanisms, biology and inhibitors of deubiquitinating enzymes. — Nat Chem Biol

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3KQ	N/Tert-1 UCHL3	Telomerase immortalized cell line	Male
CVCL_TW14	HAP1 UCHL3 (-) 1	Cancer cell line	Male
CVCL_TW15	HAP1 UCHL3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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