UCHL5

Summary

UCHL5 (ubiquitin C-terminal hydrolase L5, HGNC:19678) is a protein-coding gene on chromosome 1q31.2, encoding Ubiquitin carboxyl-terminal hydrolase isozyme L5 (Q9Y5K5). Protease that specifically cleaves ‘Lys-48’-linked polyubiquitin chains. It is a selective cancer dependency (DepMap: 31.3% of cell lines).

Enables cysteine-type deubiquitinase activity; endopeptidase inhibitor activity; and proteasome binding activity. Involved in several processes, including positive regulation of smoothened signaling pathway; protein deubiquitination; and regulation of primary metabolic process. Located in cytosol and nuclear lumen.

Source: NCBI Gene 51377 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 41 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 31.3% of screened cell lines
• MANE Select transcript: NM_001199261

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19678
Approved symbol	UCHL5
Name	ubiquitin C-terminal hydrolase L5
Location	1q31.2
Locus type	gene with protein product
Status	Approved
Aliases	UCH37, CGI-70, INO80R
Ensembl gene	ENSG00000116750
Ensembl biotype	protein_coding
OMIM	610667
Entrez	51377

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 28 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000367448, ENST00000367449, ENST00000367450, ENST00000367451, ENST00000367454, ENST00000367455, ENST00000416915, ENST00000417752, ENST00000420791, ENST00000421683, ENST00000443327, ENST00000449480, ENST00000483156, ENST00000874429, ENST00000874430, ENST00000874431, ENST00000874432, ENST00000874433, ENST00000874434, ENST00000874435, ENST00000874436, ENST00000935571, ENST00000935572, ENST00000935573, ENST00000935574, ENST00000941920, ENST00000941921, ENST00000941922, ENST00000941923

RefSeq mRNA: 17 — MANE Select: NM_001199261 NM_001199261, NM_001199262, NM_001199263, NM_001350840, NM_001350841, NM_001350842, NM_001350843, NM_001350844, NM_001350845, NM_001350846, NM_001350847, NM_001350848, NM_001350849, NM_001350850, NM_001350851, NM_001350852, NM_015984

CCDS: CCDS1378, CCDS55668, CCDS55669, CCDS55670, CCDS86041

Canonical transcript exons

ENST00000367454 — 11 exons

Exon	Start	End
ENSE00001600331	193029388	193029449
ENSE00001657775	193029179	193029309
ENSE00001700426	193023844	193023946
ENSE00001731587	193021097	193021195
ENSE00001734709	193028085	193028148
ENSE00001782511	193022926	193023036
ENSE00003482652	193051754	193051817
ENSE00003501139	193029532	193029657
ENSE00003518097	193049746	193049851
ENSE00003612524	193012254	193016395
ENSE00003905583	193059185	193059360

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 92.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.2793 / max 631.5590, expressed in 1823 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16448	26.4807	1809
16451	1.5969	1042
16450	0.8266	554
16449	0.3751	161

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	92.59	gold quality
calcaneal tendon	UBERON:0003701	91.89	gold quality
islet of Langerhans	UBERON:0000006	91.45	gold quality
body of pancreas	UBERON:0001150	91.35	gold quality
prefrontal cortex	UBERON:0000451	90.81	gold quality
adrenal tissue	UBERON:0018303	90.81	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.60	gold quality
rectum	UBERON:0001052	90.54	gold quality
monocyte	CL:0000576	90.10	gold quality
pancreas	UBERON:0001264	90.10	gold quality
mononuclear cell	CL:0000842	89.91	gold quality
leukocyte	CL:0000738	89.85	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.78	gold quality
gastrocnemius	UBERON:0001388	89.76	gold quality
muscle of leg	UBERON:0001383	89.75	gold quality
colonic epithelium	UBERON:0000397	89.48	gold quality
esophagus mucosa	UBERON:0002469	89.42	gold quality
ventricular zone	UBERON:0003053	89.25	gold quality
ganglionic eminence	UBERON:0004023	89.08	gold quality
endothelial cell	CL:0000115	88.95	gold quality
stromal cell of endometrium	CL:0002255	88.71	gold quality
heart left ventricle	UBERON:0002084	88.02	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.01	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.88	gold quality
cardiac ventricle	UBERON:0002082	87.75	gold quality
heart right ventricle	UBERON:0002080	87.71	gold quality
anterior cingulate cortex	UBERON:0009835	87.68	gold quality
cingulate cortex	UBERON:0003027	87.62	gold quality
right atrium auricular region	UBERON:0006631	87.50	gold quality
muscle organ	UBERON:0001630	87.39	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.22
E-CURD-112	yes	4.99
E-CURD-10	no	536.49

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

136 targeting UCHL5, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-338-5P	99.92	72.34	2951

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 31.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 39)

• UCH37 interacts with Smads and regulates TGF-beta signalling. (PMID:16027725)
• Upregulation of UCH37 is associated with Uterine Cervical Neoplasms (PMID:16402389)
• Neither Uch37 alone nor the Uch37-Adrm1 or Uch37-Adrm1-S1 complexes can hydrolyse di-ubiquitin efficiently; rather, incorporation into the 19S complex is required to enable processing of polyubiquitin chains. (PMID:16906146)
• These results indicate that hRpn13 (Adrm1) is essential for the activity of UCH37. (PMID:16990800)
• In human 26S proteasomes, hRpn13 appears to be important for the binding of UCH37 to the 19S complex and for efficient proteolysis. (PMID:17139257)
• In the nucleus Uch37 is also associated with the human Ino80 chromatin-remodeling complex (hINO80). (PMID:18922472)
• the crystal structure of the UCH37 catalytic domain (UCH-domain) was determined and compared with that of the other UCHs. (PMID:19836345)
• Silencing of UCH37 in A549 cells induced apoptosis. (PMID:21287580)
• a functional proteomic analysis was performed to screen UCH37-interacting proteins in hepatocellular carcinoma (HCC), and glucose-regulated protein 78 was identified as one interacting with UCH37 (PMID:21800051)
• Uch37 consists of two domains, a globular UCH-domain and a fibrous C-terminal tail. The C-terminal residues of Uch37 are implicated in Rpn13 binding. (PMID:21953935)
• our structures reveal conformationally dynamic parts of the enzyme that may play a role in the structural transition to the more active form. (PMID:21995438)
• UCH37 is associated with outcome and recurrence of ESCC and can be a novel predictor for poor prognosis of esophageal squamous cell carcinoma patients after curative resection. (PMID:22615012)
• UCH37 over-expression is associated with hepatocellular carcinoma recurrence. (PMID:23220010)
• b-AP15 is an inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. (PMID:24319254)
• High expression of UCH37 is significantly associated with epithelial ovarian cancer. (PMID:25123264)
• Data show that DEUBAD domain in RPN13 (ADRM1) activates ubiquitin thioesterase L5 (UCH-L5), and the related DEUBAD domain in INO80G (NFRKB) inhibits UCH-L5. (PMID:25702870)
• Data indicate that ubiquitin thioesterase L5 UCH37 (UCHL5) comprises a catalytic UCH domain followed by the four-helix (alpha8-alpha11) C-terminal domain. (PMID:25702872)
• These results uncover a novel mechanism for E2F1 transcriptional activation through removal of its Lys-63-linked ubiquitination by UCH37. (PMID:26396186)
• this work implicates hRpn13 and Uch37 in cell cycle progression, providing a rationale for their function in cellular proliferation and for the apoptotic effect of the hRpn13-targeting molecule RA190. (PMID:26907685)
• Our studies provide a molecular mechanism by which UCHL5 mitigates TGFbeta-1 signaling by stabilizing Smad2/Smad3. These data indicate that UCHL5 may contribute to the pathogenesis of idiopathic pulmonary fibrosis and may be a potential therapeutic target. (PMID:27604640)
• our report demonstrates significant value in targeting USP14/UCHL5 with VLX1570 in drug-resistant Waldenstrom macroglobulinemia (WM) and carries a high potential for clinical translation (PMID:27813535)
• Our study provides a new mechanism for chromatin occupancy of Tcf7 and uncovers the physiological significance of Uch37 during early vertebrate development by regulating the Wnt/beta-catenin pathway. (PMID:28198400)
• Rpn13-Rpn2 complex structural analysis shows that RA190 targets hRpn13 and Uch37 through parallel mechanisms and at proteasomes, RA190-inactivated Uch37 cannot disassemble hRpn13-bound ubiquitin chains (PMID:28598414)
• UCHL5 expression could function as a prognostic marker in pancreatic ductal adenocarcinoma, particularly at disease stages IIB to III. As UCHL5 is one of the few markers predicting increased survival, our results may be of clinical relevance. (PMID:28653876)
• UCHL5 is a promising novel prognostic marker in lymph-node-positive rectal cancer. Our results also advance the currently limited knowledge of biomarkers in colorectal cancer treatment. (PMID:28681694)
• Positive cytoplasmic UCHL5 tumor immunoexpression is linked to increased survival of patients with small (<5 cm) tumors (p = 0.001), disease stages I-II (p = 0.025), and age 66 years or older (p = 0.037). UCHL5 is thus a potential marker in gastric cancer with new prognostic relevance. (PMID:29474458)
• UCH37 maintains the homeostasis of proteasomal degradation reciprocally by assisting the recruitment of the ubiquitin receptor Rpn13 into the proteasome and by reversing ubiquitination of certain critical substrates of the 26 S proteasome. (PMID:30726867)
• Data suggest that UCHL5 can deubiquitinate distinct substrates from that of USP14 at the proteasome and regulate the ubiquitination of the proteasome itself which is tightly linked to its function. (PMID:31703099)
• LncRNA DRAIC inhibits proliferation and metastasis of gastric cancer cells through interfering with NFRKB deubiquitination mediated by UCHL5. (PMID:32351584)
• Ubiquitin Carboxyl-Terminal Hydrolases (UCHs): Potential Mediators for Cancer and Neurodegeneration. (PMID:32486284)
• Impact of Losing hRpn13 Pru or UCHL5 on Proteasome Clearance of Ubiquitinated Proteins and RA190 Cytotoxicity. (PMID:32631902)
• Proteasome-Bound UCH37/UCHL5 Debranches Ubiquitin Chains to Promote Degradation. (PMID:33156996)
• Deubiquitination and Activation of the NLRP3 Inflammasome by UCHL5 in HCV-Infected Cells. (PMID:34431717)
• UCHL5 controls beta-catenin destruction complex function through Axin1 regulation. (PMID:35256667)
• A ubiquitinome analysis to study the functional roles of the proteasome associated deubiquitinating enzymes USP14 and UCH37. (PMID:35489684)
• Deubiquitinase UCHL5 stabilizes ELK3 to potentiate cancer stemness and tumor progression in pancreatic adenocarcinoma (PAAD). (PMID:36328194)
• MAFG-AS1/MAFG positive feedback loop contributes to cisplatin resistance in bladder urothelial carcinoma through antagonistic ferroptosis. (PMID:36654385)
• The TGF-beta/UCHL5/Smad2 Axis Contributes to the Pathogenesis of Placenta Accreta. (PMID:37762005)
• UCHL5 promotes hepatocellular carcinoma progression by promoting glycolysis through activating Wnt/beta-catenin pathway. (PMID:38773433)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	uchl5	ENSDARG00000103404
mus_musculus	Uchl5	ENSMUSG00000018189
rattus_norvegicus	Uchl5	ENSRNOG00000003545
drosophila_melanogaster	Uch-L5	FBGN0011327
drosophila_melanogaster	Uch-L5R	FBGN0030370
caenorhabditis_elegans		WBGENE00006724

Paralogs (3): UCHL3 (ENSG00000118939), UCHL1 (ENSG00000154277), BAP1 (ENSG00000163930)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase isozyme L5 — Q9Y5K5 (reviewed: Q9Y5K5)

Alternative names: Ubiquitin C-terminal hydrolase UCH37, Ubiquitin thioesterase L5

All UniProt accessions (9): Q9Y5K5, H0Y4E0, H0Y4K0, H0Y636, H0Y6Y4, Q5LJA5, Q5LJA9, Q5LJB0, Q5LJB1

UniProt curated annotations — full annotation on UniProt →

Function. Protease that specifically cleaves ‘Lys-48’-linked polyubiquitin chains. Deubiquitinating enzyme associated with the 19S regulatory subunit of the 26S proteasome. Putative regulatory component of the INO80 complex; however is inactive in the INO80 complex and is activated by a transient interaction of the INO80 complex with the proteasome via ADRM1.

Subunit / interactions. Component of the 19S (PA700) regulatory complex of the 26S proteasome. Interacts with ADRM1 and NFRKB; in vitro ADRM1 and NFRKB compete for interaction with UCHL5. Component of the INO80 complex; specifically part of a complex module associated with N-terminus of INO80.

Subcellular location. Cytoplasm. Nucleus.

Activity regulation. Activated by ADRM1. Inhibited by interaction with NFRKB.

Similarity. Belongs to the peptidase C12 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y5K5-1	1	yes
Q9Y5K5-2	2
Q9Y5K5-3	3
Q9Y5K5-4	4

RefSeq proteins (17): NP_001186190, NP_001186191, NP_001186192, NP_001337769, NP_001337770, NP_001337771, NP_001337772, NP_001337773, NP_001337774, NP_001337775, NP_001337776, NP_001337777, NP_001337778, NP_001337779, NP_001337780, NP_001337781, NP_057068 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001578	Peptidase_C12_UCH	Domain
IPR017390	Ubiquitinyl_hydrolase_UCH37	Family
IPR033837	UCH37	Domain
IPR036959	Peptidase_C12_UCH_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR041507	UCH_C	Domain

Pfam: PF01088, PF18031

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 (40 total): helix 13, strand 9, modified residue 3, splice variant 3, domain 2, active site 2, site 2, chain 1, sequence variant 1, mutagenesis site 1, sequence conflict 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
3RII	X-RAY DIFFRACTION	2
3A7S	X-RAY DIFFRACTION	2.2
3TB3	X-RAY DIFFRACTION	2.3
4UEL	X-RAY DIFFRACTION	2.3
3RIS	X-RAY DIFFRACTION	2.4
9E7K	X-RAY DIFFRACTION	2.41
4UEM	X-RAY DIFFRACTION	2.82
3IHR	X-RAY DIFFRACTION	2.95
4WLP	X-RAY DIFFRACTION	3.1
4UF6	X-RAY DIFFRACTION	3.69
4UF5	X-RAY DIFFRACTION	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5K5-F1	90.32	0.74

Antibody-complex structures (SAbDab): 1 — 9E7K

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): 88 (nucleophile); 164 (proton donor); 82 (transition state stabilizer); 179 (important for enzyme activity)

Post-translational modifications (3): 289, 47, 158

Mutagenesis-validated functional residues (1):

Position	Phenotype
88	abolishes enzymatic activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2173788	Downregulation of TGF-beta receptor signaling
R-HSA-5689603	UCH proteinases

MSigDB gene sets: 284 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_FOREBRAIN_MORPHOGENESIS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_TELOMERE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_VENTRICULAR_SYSTEM_DEVELOPMENT, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_FOREBRAIN_DEVELOPMENT, RODWELL_AGING_KIDNEY_NO_BLOOD_DN

GO Biological Process (23): telomere maintenance (GO:0000723), regulation of DNA replication (GO:0006275), DNA repair (GO:0006281), regulation of DNA repair (GO:0006282), DNA recombination (GO:0006310), chromatin remodeling (GO:0006338), ubiquitin-dependent protein catabolic process (GO:0006511), protein deubiquitination (GO:0016579), lateral ventricle development (GO:0021670), midbrain development (GO:0030901), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), regulation of chromosome organization (GO:0033044), positive regulation of DNA repair (GO:0045739), positive regulation of smoothened signaling pathway (GO:0045880), positive regulation of DNA-templated transcription (GO:0045893), regulation of embryonic development (GO:0045995), forebrain morphogenesis (GO:0048853), regulation of cell cycle (GO:0051726), regulation of DNA strand elongation (GO:0060382), regulation of proteasomal protein catabolic process (GO:0061136), positive regulation of telomere maintenance in response to DNA damage (GO:1904507), proteolysis (GO:0006508), DNA damage response (GO:0006974)

GO Molecular Function (8): RNA binding (GO:0003723), cysteine-type deubiquitinase activity (GO:0004843), endopeptidase inhibitor activity (GO:0004866), proteasome binding (GO:0070628), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (7): proteasome complex (GO:0000502), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), Ino80 complex (GO:0031011)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TGF-beta receptor signaling activates SMADs	1
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	3
regulation of DNA metabolic process	3
cellular anatomical structure	3
DNA repair	2
anatomical structure development	2
nuclear lumen	2
telomere organization	1
DNA replication	1
DNA damage response	1
regulation of cellular response to stress	1
chromatin organization	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
telencephalon development	1
ventricular system development	1
brain development	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
negative regulation of proteasomal protein catabolic process	1
negative regulation of ubiquitin-dependent protein catabolic process	1
regulation of organelle organization	1
chromosome organization	1
regulation of DNA repair	1
positive regulation of response to stimulus	1
positive regulation of DNA metabolic process	1
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1
positive regulation of signal transduction	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
embryo development	1
regulation of multicellular organismal development	1
anatomical structure morphogenesis	1
forebrain development	1
brain morphogenesis	1
cell cycle	1
regulation of cellular process	1

Protein interactions and networks

STRING

2408 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UCHL5	ADRM1	Q16186	999
UCHL5	PSMD4	P55036	987
UCHL5	SMAD7	O15105	982
UCHL5	PSMD14	O00487	945
UCHL5	USP14	P54578	936
UCHL5	NFRKB	Q6P4R8	888
UCHL5	PSMD8	P48556	882
UCHL5	HAUS7	Q99871	808
UCHL5	PSMC4	P43686	799
UCHL5	ZUP1	Q96AP4	795
UCHL5	USP5	P45974	768
UCHL5	COPS5	Q92905	743
UCHL5	STAMBP	O95630	723
UCHL5	PSMD7	P51665	701
UCHL5	USP7	Q93009	694

IntAct

167 interactions, top by confidence:

A	B	Type	Score
UCHL5	ADRM1	psi-mi:“MI:0915”(physical association)	0.970
ADRM1	UCHL5	psi-mi:“MI:0915”(physical association)	0.970
ADRM1	UCHL5	psi-mi:“MI:0407”(direct interaction)	0.970
UCHL5	ADRM1	psi-mi:“MI:0407”(direct interaction)	0.970
ADRM1	UCHL5	psi-mi:“MI:0403”(colocalization)	0.970
UCHL5	ADRM1	psi-mi:“MI:0403”(colocalization)	0.970
INO80E	YY1	psi-mi:“MI:0914”(association)	0.900
UCHL5	NFRKB	psi-mi:“MI:0915”(physical association)	0.890
NFRKB	UCHL5	psi-mi:“MI:0915”(physical association)	0.890
NFRKB	UCHL5	psi-mi:“MI:0407”(direct interaction)	0.890
UCHL5	NFRKB	psi-mi:“MI:0407”(direct interaction)	0.890
UCHL5	NFRKB	psi-mi:“MI:0914”(association)	0.890
PSMD2	UCHL5	psi-mi:“MI:0915”(physical association)	0.890
UCHL5	PSMD4	psi-mi:“MI:0407”(direct interaction)	0.860
UCHL5	PSMD11	psi-mi:“MI:0914”(association)	0.840

BioGRID (726): UCHL5 (Affinity Capture-MS), PLA2G2A (Biochemical Activity), UCHL5 (Two-hybrid), UCHL5 (Two-hybrid), UCHL5 (Two-hybrid), UCHL5 (Biochemical Activity), UCHL5 (Affinity Capture-Western), UCHL5 (Biochemical Activity), UCHL5 (Affinity Capture-MS), UCHL5 (Affinity Capture-MS), PSMD1 (Affinity Capture-MS), PSMD13 (Affinity Capture-MS), INO80C (Affinity Capture-MS), FHOD1 (Affinity Capture-MS), NFRKB (Affinity Capture-MS)

ESM2 similar proteins: A0JN27, A2ADY9, D3K5L7, D3Z7P3, E2R222, G3MWR8, O70133, O94925, O94973, P13264, P18484, P97834, Q06AT3, Q08211, Q0VCK5, Q13042, Q13098, Q15645, Q28141, Q28F89, Q2KI56, Q2TBV5, Q3MHJ2, Q3UA06, Q497D6, Q5NVP9, Q5R874, Q5RBN9, Q5TDH0, Q5XHZ9, Q5XIT1, Q5ZJB7, Q6AYU1, Q6NRB5, Q6NRT5, Q6PER3, Q6TH22, Q7RTP6, Q7ZYA7, Q86TJ2

Diamond homologs: A1L2G3, A2VDM8, B0W2R4, B3MIV9, B3NPV7, B4GAM2, B4HST0, B4JW98, B4KT51, B4LQ24, B4P6P6, B4QHH0, C4A0D9, D3ZHS6, O04482, Q06AT3, Q09444, Q17N72, Q291J4, Q52L14, Q54N38, Q5F3N6, Q66JB6, Q7K5N4, Q8IIJ6, Q92560, Q99PU7, Q9FFF2, Q9UUB6, Q9WUP7, Q9XSJ0, Q9Y5K5, P09936, Q00981, Q9R0P9, P50103, Q60HC8, Q9GM50, P35122, Q2TBG8

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
UCHL5	up-regulates	SMAD2	deubiquitination
UCHL5	up-regulates	SMAD7	binding
UCHL5	“up-regulates quantity by stabilization”	TGFBR1	binding
UCHL5	“up-regulates activity”	SMAD2	deubiquitination
UCHL5	“up-regulates activity”	SMAD3	deubiquitination
UCHL5	“form complex”	“INO80 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 132 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of activated PAK-2p34 by proteasome mediated degradation	28	78.8×	5e-48
Regulation of ornithine decarboxylase (ODC)	28	76.9×	1e-47
Vpu mediated degradation of CD4	28	75.1×	2e-47
Autodegradation of the E3 ubiquitin ligase COP1	28	75.1×	2e-47
Ubiquitin-dependent degradation of Cyclin D	28	75.1×	2e-47
Antigen processing: Ub, ATP-independent proteasomal degradation	13	75.0×	3e-22
Cross-presentation of soluble exogenous antigens (endosomes)	28	71.8×	1e-46
Vif-mediated degradation of APOBEC3G	28	71.8×	1e-46

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of telomere maintenance in response to DNA damage	10	92.8×	2e-16
regulation of DNA strand elongation	10	87.0×	3e-16
regulation of chromosome organization	10	77.4×	1e-15
positive regulation of DNA repair	11	32.6×	2e-12
regulation of DNA replication	10	30.3×	7e-11
regulation of embryonic development	10	27.3×	2e-10
DNA recombination	9	25.1×	4e-09
regulation of DNA repair	10	22.8×	1e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2104 predictions. Top by Δscore:

Variant	Effect	Δscore
1:193020382:C:CC	acceptor_gain	1.0000
1:193021091:ACTT:A	donor_loss	1.0000
1:193021092:CTT:C	donor_loss	1.0000
1:193021093:TTA:T	donor_loss	1.0000
1:193021094:TACC:T	donor_loss	1.0000
1:193021095:A:AC	donor_gain	1.0000
1:193021095:AC:A	donor_gain	1.0000
1:193021096:C:CG	donor_gain	1.0000
1:193021096:CC:C	donor_gain	1.0000
1:193021096:CCT:C	donor_gain	1.0000
1:193021096:CCTT:C	donor_gain	1.0000
1:193021096:CCTTT:C	donor_gain	1.0000
1:193021192:CAAT:C	acceptor_gain	1.0000
1:193021193:AATC:A	acceptor_loss	1.0000
1:193021195:TCT:T	acceptor_loss	1.0000
1:193021196:C:CC	acceptor_gain	1.0000
1:193021196:CTGA:C	acceptor_loss	1.0000
1:193021197:T:A	acceptor_loss	1.0000
1:193022921:CATA:C	donor_loss	1.0000
1:193022922:ATAC:A	donor_loss	1.0000
1:193022923:TACCT:T	donor_loss	1.0000
1:193022924:ACCT:A	donor_loss	1.0000
1:193022925:C:A	donor_loss	1.0000
1:193023037:CTC:C	acceptor_gain	1.0000
1:193023039:CCT:C	acceptor_gain	1.0000
1:193023041:T:C	acceptor_gain	1.0000
1:193023041:T:TC	acceptor_gain	1.0000
1:193023825:TAGAA:T	donor_gain	1.0000
1:193023826:A:AC	donor_gain	1.0000
1:193023826:AGAAA:A	donor_gain	1.0000

AlphaMissense

2191 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:193016395:C:G	A316P	1.000
1:193021116:A:G	L309S	1.000
1:193021132:C:G	A304P	1.000
1:193021169:A:C	N291K	1.000
1:193021169:A:T	N291K	1.000
1:193021173:T:G	H290P	1.000
1:193021174:G:C	H290D	1.000
1:193021178:C:A	R288S	1.000
1:193021178:C:G	R288S	1.000
1:193021179:C:A	R288M	1.000
1:193021179:C:G	R288T	1.000
1:193021180:T:C	R288G	1.000
1:193021181:T:A	R287S	1.000
1:193021181:T:G	R287S	1.000
1:193021182:C:G	R287T	1.000
1:193023911:G:T	A222D	1.000
1:193023912:C:G	A222P	1.000
1:193023914:A:C	M221R	1.000
1:193023917:A:G	L220S	1.000
1:193023919:A:C	N219K	1.000
1:193023919:A:T	N219K	1.000
1:193023922:A:C	F218L	1.000
1:193023922:A:T	F218L	1.000
1:193023923:A:G	F218S	1.000
1:193023924:A:C	F218V	1.000
1:193023924:A:G	F218L	1.000
1:193023924:A:T	F218I	1.000
1:193028093:C:A	R207S	1.000
1:193028093:C:G	R207S	1.000
1:193028103:A:T	I204K	1.000

dbSNP variants (sampled 300 via entrez): RS1000159985 (1:193019515 T>C), RS1000277354 (1:193044204 A>G), RS1000280996 (1:193031489 A>G), RS1000553659 (1:193055146 C>T), RS1000714458 (1:193048343 G>C), RS1000927350 (1:193057114 T>C,G), RS1000937882 (1:193041288 T>A), RS1001013479 (1:193042622 T>C), RS1001031332 (1:193049430 C>A), RS1001055412 (1:193027609 C>T), RS1001129692 (1:193034850 C>A), RS1001180595 (1:193036727 T>C,G), RS1001258022 (1:193018362 G>A,C), RS1001278344 (1:193030378 A>C), RS1001289768 (1:193030758 A>C)

Disease associations

OMIM: gene MIM:610667 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000861_9	Cannabis dependence	5.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3407316 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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

Binding affinities (BindingDB)

4 measured of 6 human assays (7 total across all organisms); most potent 4 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

ChEMBL bioactivities

5 potent at pChembl≥5 of 15 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.24	Kd	57.57	nM	CHEMBL5653589
7.24	ED50	57.57	nM	CHEMBL5653589
7.05	Kd	90	nM	MOLIBRESIB
6.89	IC50	130	nM	MOLIBRESIB
5.82	Kd	1500	nM	CHEMBL4441423

PubChem BioAssay actives

4 with measured affinity, of 60 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149722: Binding affinity to human UCHL5 incubated for 45 mins by Kinobead based pull down assay	kd	0.0576	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179244: Binding affinity against UCHL5 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0900	uM
(3E,5E)-3,5-bis[(4-fluoro-3-nitrophenyl)methylidene]-1-prop-2-enoylazepan-4-one	1930819: Inhibition of human his tagged UCHL5 assessed as dissociation constant by SPR analysis	kd	1.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	6
bisphenol A	affects cotreatment, affects expression, increases abundance, decreases expression, decreases methylation (+1 more)	4
methylmercuric chloride	increases expression, affects cotreatment	3
bisphenol S	affects expression, decreases methylation, increases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
Cisplatin	affects binding, increases reaction, increases phosphorylation	2
Tretinoin	decreases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
ginger extract	increases abundance, affects cotreatment, affects expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
beta-methylcholine	affects expression	1
K 7174	decreases expression	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
dorsomorphin	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Irinotecan	decreases expression	1
Arsenic Trioxide	increases expression	1
Arsenic	increases abundance, increases expression	1
Coumestrol	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Diacetyl	increases expression	1
Diazinon	increases methylation	1
Dinitrochlorobenzene	affects binding	1
Ethyl Methanesulfonate	decreases expression	1
Folic Acid	decreases expression	1

ChEMBL screening assays

31 unique, capped per target: 31 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3412385	Binding	Inhibition of GST-tagged UCHL5 (unknown origin) using Ub-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	Synthesis, characterization, and optimization for in vivo delivery of a nonselective isopeptidase inhibitor as new antineoplastic agent. — J Med Chem

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 1 telomerase immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8AA	Abcam Raji UCHL5 KO	Cancer cell line	Male
CVCL_C0B4	Abcam THP-1 UCHL5 KO	Cancer cell line	Male
CVCL_C3KR	N/Tert-1 UCHL5	Telomerase immortalized cell line	Male
CVCL_C7CS	Abcam PC-3 UCHL5 KO	Cancer cell line	Male
CVCL_E1FW	Abcam HEK293 UCHL5 KO	Transformed cell line	Female
CVCL_E2N8	HAP1 UCHL5 (-) 1	Cancer cell line	Male
CVCL_E2N9	HAP1 UCHL5 (-) 2	Cancer cell line	Male
CVCL_E2NA	HAP1 UCHL5 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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