USP14

Summary

USP14 (ubiquitin specific peptidase 14, HGNC:12612) is a protein-coding gene on chromosome 18p11.32, encoding Ubiquitin carboxyl-terminal hydrolase 14 (P54578). Proteasome-associated deubiquitinase which releases ubiquitin from the proteasome targeted ubiquitinated proteins.

This gene encodes a member of the ubiquitin-specific processing (UBP) family of proteases that is a deubiquitinating enzyme (DUB) with His and Cys domains. This protein is located in the cytoplasm and cleaves the ubiquitin moiety from ubiquitin-fused precursors and ubiquitinylated proteins. Mice with a mutation that results in reduced expression of the ortholog of this protein are retarded for growth, develop severe tremors by 2 to 3 weeks of age followed by hindlimb paralysis and death by 6 to 10 weeks of age. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 9097 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic disease (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 68 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_005151

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12612
Approved symbol	USP14
Name	ubiquitin specific peptidase 14
Location	18p11.32
Locus type	gene with protein product
Status	Approved
Aliases	TGT, Ubp6
Ensembl gene	ENSG00000101557
Ensembl biotype	protein_coding
OMIM	607274
Entrez	9097

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000261601, ENST00000383589, ENST00000400266, ENST00000578786, ENST00000578942, ENST00000580410, ENST00000581983, ENST00000582707, ENST00000583119, ENST00000873770, ENST00000873771, ENST00000873772, ENST00000936898, ENST00000947712

RefSeq mRNA: 2 — MANE Select: NM_005151 NM_001037334, NM_005151

CCDS: CCDS32780, CCDS32781

Canonical transcript exons

ENST00000261601 — 16 exons

Exon	Start	End
ENSE00001208675	178933	179037
ENSE00001208689	211133	214629
ENSE00002691455	158557	158714
ENSE00003472267	180236	180339
ENSE00003490322	166787	166819
ENSE00003525154	203098	203190
ENSE00003558418	197616	197696
ENSE00003569027	199202	199316
ENSE00003596595	196637	196767
ENSE00003609763	209971	210031
ENSE00003622515	198047	198132
ENSE00003624683	204564	204692
ENSE00003645471	210386	210493
ENSE00003667652	202880	202945
ENSE00003682471	163308	163453
ENSE00003685280	192842	192900

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 97.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 59.5051 / max 458.0538, expressed in 1826 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169044	57.6148	1825
169040	1.5303	910
169041	0.3600	155

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.56	gold quality
tibialis anterior	UBERON:0001385	96.18	gold quality
deltoid	UBERON:0001476	95.91	gold quality
pons	UBERON:0000988	95.89	gold quality
diaphragm	UBERON:0001103	95.81	gold quality
trabecular bone tissue	UBERON:0002483	95.77	gold quality
trigeminal ganglion	UBERON:0001675	95.65	gold quality
oocyte	CL:0000023	95.52	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.51	gold quality
skin of hip	UBERON:0001554	95.39	gold quality
dorsal root ganglion	UBERON:0000044	95.38	gold quality
superior vestibular nucleus	UBERON:0007227	95.34	gold quality
gluteal muscle	UBERON:0002000	95.30	gold quality
biceps brachii	UBERON:0001507	95.13	gold quality
heart right ventricle	UBERON:0002080	94.91	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.82	gold quality
skeletal muscle tissue	UBERON:0001134	94.80	gold quality
parietal lobe	UBERON:0001872	94.77	gold quality
gingival epithelium	UBERON:0001949	94.76	gold quality
cartilage tissue	UBERON:0002418	94.71	gold quality
entorhinal cortex	UBERON:0002728	94.70	gold quality
body of tongue	UBERON:0011876	94.70	gold quality
corpus callosum	UBERON:0002336	94.63	gold quality
postcentral gyrus	UBERON:0002581	94.59	gold quality
sperm	CL:0000019	94.58	gold quality
superficial temporal artery	UBERON:0001614	94.56	gold quality
substantia nigra pars compacta	UBERON:0001965	94.54	gold quality
vastus lateralis	UBERON:0001379	94.51	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.51	gold quality
saphenous vein	UBERON:0007318	94.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6386	no	673.20
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

97 targeting USP14, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4271	99.88	68.32	2244
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-204-5P	99.79	71.62	2439

Literature-anchored findings (GeneRIF, showing 40)

• the catalytic cleft leading to the active site of USP14 is blocked by two surface loops. Binding by ubiquitin induces a significant conformational change thereby allowing access of the ubiquitin C-terminus to the active site. (PMID:16211010)
• Results show the overall survival rate was worse in patients with a high USP14/TGT60 kD expression level and suggest that USP14/TGT60 kD also controls the fate of proteins that regulate tumor invasion and metastasis. (PMID:16465409)
• Neuronal expression of full-length USP14 is able to restore the levels of monomeric ubiquitin in the brains of transgenic ataxia mice. (PMID:17079671)
• USP14 were over-expressed in ovarian serous cystadenocarcinoma tissues, suggesting that the activity of ubiquitin-proteasome system is obviously enhanced in ovarian cancer. (PMID:17553343)
• These findings suggest that USP14 is a novel player in the unfolded protein response by serving as a physiological inhibitor of ER-associated degradation under the non-stressed condition. (PMID:19135427)
• Data from transgenic mice define a critical role for Usp14 at mammalian synapses and suggest a requirement for local ubiquitin recycling by the proteasome to control the development and function of neuromuscular junctions. (PMID:19726649)
• High Ubiquitin-specific protease 14 expression associated with intrahepatic cholangiocarcinoma cell differentiation. (PMID:21627382)
• the decrease in proteolysis of proteasomal substrates during aging is independent of the increased USP14 activity and that the reciprocal regulation of USP14 and proteasomal catalytic activity may be necessary to maintain cellular ubiquitin homeostasis. (PMID:23291607)
• overexpression of HA-USP14 increased the LPS-, TNFalpha-, or Escherichia coli-induced IL-8 release in human lung epithelial cells. (PMID:23615914)
• Downregulation of USP14 expression arrested the cell cycle, which may be related to beta-catenin degradation. (PMID:23702845)
• b-AP15 is an inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. (PMID:24319254)
• MiR-4782-3p inhibited cell proliferation in NSCLC by targeting USP14, ZEB2 and XIAP. (PMID:24556800)
• our findings suggest that USP14 is involved in the progression of epithelial ovarian cancer (PMID:25429837)
• our findings suggested that USP14 is involved in the progression of hepatocellular carcinoma(HCC) and may be a useful therapeutic target in HCC (PMID:26397990)
• Akt-mediated phosphorylation of USP14 at Ser432, which normally blocks its catalytic site in the inactive conformation, activates its deubiquitinating activity in vitro and in cells. (PMID:26523394)
• USP14 participates in CAM-DR of MM through acting as a bridge between Bcl-xl apoptotic pathway and Wnt-signaling pathways and may be represented as a good candidate for pursuing clinical trials in MM. (PMID:26710889)
• Increased USP14 expression in patients with breast cancer was associated with a poorer prognosis. (PMID:26712154)
• Results show that USP14 mRNA is overexpressed in hepatocellular carcinoma (HCC) tissues and inversely correlates with miR-4782-3p level which binds to USP14 3’UTR to regulate its expression. (PMID:26782643)
• Cell surface ubiquitination precedes endocytosis, after which USP14 acts as an ubiquitin-binding protein that targets the ubiquitinated GABA B receptor to lysosomal degradation and promotes its deubiquitination. (PMID:26817839)
• Results found USP14 amplification and overexpression in many different cancers. Its overexpression in low-expression cell lines promoted cell proliferation and migration, whereas its downregulation suppressed tumor cell proliferation, increased apoptosis rate, and decreased cell migration and invasion suggesting an oncogenic role in various types of cancer. (PMID:26938858)
• USP14 shows a marked preference for ubiquitin-cyclin B conjugates that carry more than one ubiquitin modification or chain (PMID:27074503)
• our results demonstrated that vimentin in human GC tissues and cell lines was upregulated due to its de-ubiquitination after interactions with USP14 and miR-320a, which could promote the aggressiveness of GC cells. (PMID:27448976)
• USP14 regulates autophagy by negatively controlling K63 ubiquitination of Beclin 1 (PMID:27542828)
• Ubiquitin-specific protease 14 regulates cell proliferation and apoptosis in oral squamous cell carcinoma (PMID:27592452)
• USP14 plays an important role in the progression and metastasis of esophageal squamous cell carcinoma. (PMID:27629392)
• 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)
• USP14 promotes prostate cancer progression. (PMID:28151478)
• These findings suggested that USP14 induces NF-kappaB activity and ERK1/2 phosphorylation triggered by microbial infection. (PMID:28364380)
• Usp14 and Ube3c cycle together on and off proteasomes, and the presence of ubiquitinated substrates promotes their association. This mechanism enables proteasome activity to adapt to the supply of substrates. (PMID:28396413)
• without a ubiquitinated substrate present, Usp14 suppresses multiple proteasomal activities, especially basal ATP consumption and degradation of non-ubiquitinated proteins. These allosteric effects thus reduce ATP hydrolysis by inactive proteasomes and nonspecific proteolysis and enhance proteasomal specificity for ubiquitinated proteins. (PMID:28416611)
• Study detected elevated USP14 expression at both mRNA and protein levels, and was significantly associated with distant metastasis. (PMID:28509417)
• By displacing USP14, TRIM11 changes proteasome composition and suppresses both catalytic and non-catalytic effects of USP14 (PMID:29581427)
• Data show that ubiquitin-specific protease 14 (USP14) is a direct target of hsa-miR-124a, and that hsa-miR-124a inhibits stemness. (PMID:29702194)
• Our results provide a rationale for targeting the proteasome-associated DUB USP14 to treat and combat melanomas. (PMID:29703842)
• USP14 directly interacted with RNF168, which depended on the MIU1 domain of RNF168. These findings identify USP14 as a novel substrate of autophagy and regulation of RNF168-dependent Ubiquitination and TP53BP1 recruitment by USP14 as a critical link between DNA damage repair and autophagy. (PMID:29995557)
• USP14 may function as a common denominator in the compensatory negative feedback between the two major proteolytic processes in the cell. (PMID:30021169)
• genetic and pharmacological inhibition of USP14 promotes mitophagy. (PMID:30249595)
• USP14 levels were significantly increased in gastric cancer (GC) tissues compared to the paired normal tissues. USP14 level was an independent prognostic factor for DFS in GC patients. Its knockdown sensitized GC cells to cisplatin by triggering cisplatin-induced apoptosis via impeding Akt and ERK signaling pathways. (PMID:30296012)
• USP14 acts as a negative regulator in antiviral response through deubiquitinating K63-linked RIG-I (PMID:30466171)
• The proteasome-associated deubiquitinating enzyme Usp14/UBP6 contains an N-terminal ubiquitin-like UBL domain and is an important regulator of proteasomal activity. Usp14 by itself represses multiple proteasomal activities but, upon binding a ubiquitin chain, Usp14 promotes ubiquitin-conjugate degradation. Usp14’s UBL domain alone mimics this activation of proteasomes by ubiquitin chains. (PMID:30487212)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp14	ENSDARG00000025889
mus_musculus	Usp14	ENSMUSG00000047879
rattus_norvegicus	Usp14	ENSRNOG00000014981
drosophila_melanogaster	Usp14	FBGN0032216
caenorhabditis_elegans		WBGENE00006856

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), 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 14 — P54578 (reviewed: P54578)

Alternative names: Deubiquitinating enzyme 14, Ubiquitin thioesterase 14, Ubiquitin-specific-processing protease 14

All UniProt accessions (5): P54578, A6NJA2, J3KS55, J3QQT6, R4GNB0

UniProt curated annotations — full annotation on UniProt →

Function. Proteasome-associated deubiquitinase which releases ubiquitin from the proteasome targeted ubiquitinated proteins. Ensures the regeneration of ubiquitin at the proteasome. Is a reversibly associated subunit of the proteasome and a large fraction of proteasome-free protein exists within the cell. Required for the degradation of the chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis. Also serves as a physiological inhibitor of endoplasmic reticulum-associated degradation (ERAD) under the non-stressed condition by inhibiting the degradation of unfolded endoplasmic reticulum proteins via interaction with ERN1. Indispensable for synaptic development and function at neuromuscular junctions (NMJs). Plays a role in the innate immune defense against viruses by stabilizing the viral DNA sensor CGAS and thus inhibiting its autophagic degradation. Inhibits OPTN-mediated selective autophagic degradation of KDM4D and thereby negatively regulates H3K9me2 and H3K9me3.

Subunit / interactions. Homodimer (Potential). Associates with the 26S proteasome. Interacts with FANCC, CXCR4 and ERN1. Interacts with TRIM14; this interaction recruits USP14 to cleave ubiquitin chains of CGAS and KDM4D.

Subcellular location. Cytoplasm. Cell membrane.

Similarity. Belongs to the peptidase C19 family. USP14/UBP6 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P54578-1	1	yes
P54578-2	2
P54578-3	3

RefSeq proteins (2): NP_001032411, NP_005142* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR001394	Peptidase_C19_UCH	Domain
IPR018200	USP_CS	Conserved_site
IPR019954	Ubiquitin_CS	Conserved_site
IPR028889	USP	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR044635	UBP14-like	Family

Pfam: PF00443

UniProt features (52 total): strand 22, helix 12, modified residue 8, turn 3, domain 2, splice variant 2, active site 2, chain 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
9F6G	X-RAY DIFFRACTION	1.5
6IIK	X-RAY DIFFRACTION	1.97
6IIL	X-RAY DIFFRACTION	2.2
6IIM	X-RAY DIFFRACTION	2.21
6IIN	X-RAY DIFFRACTION	2.53
6LVS	X-RAY DIFFRACTION	2.73
9F19	X-RAY DIFFRACTION	2.75
7W37	ELECTRON MICROSCOPY	3
7W38	ELECTRON MICROSCOPY	3.1
2AYN	X-RAY DIFFRACTION	3.2
7W39	ELECTRON MICROSCOPY	3.2
7W3G	ELECTRON MICROSCOPY	3.2
7W3H	ELECTRON MICROSCOPY	3.2
7W3F	ELECTRON MICROSCOPY	3.3
7W3C	ELECTRON MICROSCOPY	3.4
2AYO	X-RAY DIFFRACTION	3.5
7W3A	ELECTRON MICROSCOPY	3.5
7W3I	ELECTRON MICROSCOPY	3.5
7W3J	ELECTRON MICROSCOPY	3.5
7W3M	ELECTRON MICROSCOPY	3.5
7W3B	ELECTRON MICROSCOPY	3.6
7W3K	ELECTRON MICROSCOPY	3.6
5GJQ	ELECTRON MICROSCOPY	4.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54578-F1	82.45	0.44

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): 114 (nucleophile); 435 (proton acceptor)

Post-translational modifications (8): 302, 432, 449, 52, 143, 148, 235, 237

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases
R-HSA-9758274	Regulation of NF-kappa B signaling

MSigDB gene sets: 249 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOCC_CELL_SURFACE, WONG_PROTEASOME_GENE_MODULE, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS

GO Biological Process (12): inflammatory response (GO:0006954), chemical synaptic transmission (GO:0007268), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), innate immune response (GO:0045087), regulation of chemotaxis (GO:0050920), regulation of proteasomal protein catabolic process (GO:0061136), protein K48-linked deubiquitination (GO:0071108), negative regulation of ERAD pathway (GO:1904293), negative regulation of ubiquitin-dependent protein catabolic process (GO:2000059), immune system process (GO:0002376), proteolysis (GO:0006508), protein deubiquitination (GO:0016579)

GO Molecular Function (10): cysteine-type endopeptidase activity (GO:0004197), cysteine-type deubiquitinase activity (GO:0004843), endopeptidase inhibitor activity (GO:0004866), K63-linked deubiquitinase activity (GO:0061578), proteasome binding (GO:0070628), deubiquitinase activity (GO:0101005), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (13): proteasome complex (GO:0000502), nucleolus (GO:0005730), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), cytoplasmic vesicle (GO:0031410), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), presynaptic cytosol (GO:0099523), membrane (GO:0016020), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Deubiquitination	1
TAK1-dependent IKK and NF-kappa-B activation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
ubiquitin-dependent protein catabolic process	2
proteasomal protein catabolic process	2
endopeptidase activity	2
cysteine-type peptidase activity	2
deubiquitinase activity	2
defense response	1
anterograde trans-synaptic signaling	1
immune response	1
defense response to symbiont	1
chemotaxis	1
regulation of response to external stimulus	1
regulation of locomotion	1
regulation of protein catabolic process	1
protein deubiquitination	1
ERAD pathway	1
negative regulation of proteasomal protein catabolic process	1
negative regulation of response to endoplasmic reticulum stress	1
regulation of ERAD pathway	1
negative regulation of protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
biological_process	1
protein metabolic process	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
protein-containing complex binding	1
ubiquitin-like protein peptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
intracellular protein-containing complex	1
endopeptidase complex	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

3180 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP14	TRIM14	Q14142	991
USP14	PSMD14	O00487	969
USP14	QTRT1	Q9BXR0	962
USP14	ADRM1	Q16186	938
USP14	UCHL5	Q9Y5K5	936
USP14	PSMD4	P55036	902
USP14	ZUP1	Q96AP4	871
USP14	USP6	P35125	868
USP14	PSMD2	Q13200	868
USP14	USP5	P45974	844
USP14	PSMC4	P43686	817
USP14	UCHL1	P09936	811
USP14	USP7	Q93009	811
USP14	COPS5	Q92905	810
USP14	PSMD11	O00231	794

IntAct

58 interactions, top by confidence:

A	B	Type	Score
UCHL5	PSMD11	psi-mi:“MI:0914”(association)	0.840
PSMD2	PSMD11	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
USP14	PSMD11	psi-mi:“MI:0914”(association)	0.530
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
USP14	PPP3CA	psi-mi:“MI:0915”(physical association)	0.460
PPP3CA	USP14	psi-mi:“MI:0915”(physical association)	0.460
USP14	PPP3CA	psi-mi:“MI:0403”(colocalization)	0.460
USP14	HSPD1	psi-mi:“MI:0915”(physical association)	0.400
USP14	CNTN1	psi-mi:“MI:0915”(physical association)	0.400
USP14	UBE2V2	psi-mi:“MI:0915”(physical association)	0.370
USP14	SPG11	psi-mi:“MI:0915”(physical association)	0.370
Psmd6	MIF4GD	psi-mi:“MI:0914”(association)	0.350
PSMC1	ZNF561	psi-mi:“MI:0914”(association)	0.350
UBE3A	IGLC7	psi-mi:“MI:0914”(association)	0.350
UBE3A	TXNL1	psi-mi:“MI:0914”(association)	0.350
NCF1	GRB2	psi-mi:“MI:0914”(association)	0.350
USP14	AHNAK	psi-mi:“MI:0914”(association)	0.350
USP14	Nudcd1	psi-mi:“MI:0914”(association)	0.350
USP7		psi-mi:“MI:0914”(association)	0.350
TAGLN	LOC392647	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
PSMC2	PSMD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (718): USP14 (Affinity Capture-RNA), USP14 (Affinity Capture-RNA), ARFIP1 (Co-fractionation), CCDC22 (Co-fractionation), CHMP7 (Co-fractionation), HSPB1 (Co-fractionation), NAPRT (Co-fractionation), NDRG1 (Co-fractionation), PSMC3 (Co-fractionation), PSMC5 (Co-fractionation), PSMD1 (Co-fractionation), PSMD11 (Co-fractionation), PSMD12 (Co-fractionation), PSMD13 (Co-fractionation), PSMD14 (Co-fractionation)

ESM2 similar proteins: A0A0R4IB93, A1CEK7, A1DFN6, A1Z7K9, A2QW83, A4RF51, E1BMF7, E1BY77, F1QFS9, F6V6I0, G0SAK8, O48534, P0C581, P38237, P40826, P43593, P45974, P54201, P54578, P56399, P60051, Q09879, Q0CJU7, Q0IIF7, Q0UPL5, Q11119, Q17361, Q1E873, Q2GSV2, Q2ULU6, Q3V0C5, Q4VSI4, Q4WHP6, Q5BBL5, Q5BKP2, Q5R407, Q5ZM45, Q6A4J8, Q6U7I1, Q76LT8

Diamond homologs: A6QR55, A6ZY34, A7TGY3, A7Z056, B2GUX4, B2GUZ1, B3LGK1, D6RBM5, E9Q9U0, E9QG68, F6Z5C0, F8VPZ3, G5E8G2, G5E8I7, M9PD06, O22207, O57429, O60079, O75604, O88623, O94966, P32571, P35123, P35125, P39538, P39944, P40818, P40826, P45974, P51784, P54578, P56399, P60051, Q01988, Q0E2F9, Q0IIF7, Q13107, Q2HJE4, Q2KHV7, Q2KJ72

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
AKT	“up-regulates activity”	USP14	phosphorylation
AKT1	“up-regulates activity”	USP14	phosphorylation
USP14	“up-regulates quantity by stabilization”	CXCR4	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 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	10	73.3×	4e-15
Regulation of ornithine decarboxylase (ODC)	10	71.5×	4e-15
Vpu mediated degradation of CD4	10	69.9×	4e-15
Autodegradation of the E3 ubiquitin ligase COP1	10	69.9×	4e-15
Ubiquitin-dependent degradation of Cyclin D	10	69.9×	4e-15
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	11	68.9×	9e-16
Cross-presentation of soluble exogenous antigens (endosomes)	10	66.8×	5e-15
Vif-mediated degradation of APOBEC3G	10	66.8×	5e-15

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	11	13.7×	1e-07
ubiquitin-dependent protein catabolic process	7	12.4×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	43
Likely benign	7
Benign	5

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1064693	NM_005151.4(USP14):c.233_236del (p.Leu78fs)	Pathogenic

SpliceAI

2362 predictions. Top by Δscore:

Variant	Effect	Δscore
18:163302:TTGCA:T	acceptor_loss	1.0000
18:163303:TGCA:T	acceptor_loss	1.0000
18:163305:CAGTT:C	acceptor_loss	1.0000
18:163306:A:AG	acceptor_gain	1.0000
18:163306:AGT:A	acceptor_loss	1.0000
18:163307:G:GG	acceptor_gain	1.0000
18:163307:GT:G	acceptor_gain	1.0000
18:163307:GTT:G	acceptor_gain	1.0000
18:163307:GTTA:G	acceptor_gain	1.0000
18:163307:GTTAC:G	acceptor_gain	1.0000
18:163440:G:GT	donor_gain	1.0000
18:163450:AAAG:A	donor_loss	1.0000
18:163452:AG:A	donor_loss	1.0000
18:163453:GGTA:G	donor_loss	1.0000
18:163454:GTA:G	donor_loss	1.0000
18:163455:T:G	donor_loss	1.0000
18:166784:CAGGA:C	acceptor_loss	1.0000
18:166815:AAAAT:A	donor_gain	1.0000
18:166816:AAAT:A	donor_gain	1.0000
18:166817:AAT:A	donor_gain	1.0000
18:166818:AT:A	donor_gain	1.0000
18:166820:G:GA	donor_loss	1.0000
18:166820:G:GG	donor_gain	1.0000
18:166822:AAGTA:A	donor_loss	1.0000
18:178931:AG:A	acceptor_gain	1.0000
18:178932:GG:G	acceptor_gain	1.0000
18:178932:GGGA:G	acceptor_gain	1.0000
18:179025:G:GG	donor_gain	1.0000
18:179035:GCT:G	donor_gain	1.0000
18:179036:CT:C	donor_gain	1.0000

AlphaMissense

3277 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:163316:A:G	K9E	1.000
18:163319:T:A	W10R	1.000
18:163319:T:C	W10R	1.000
18:163389:T:C	L33P	1.000
18:163407:T:A	V39D	1.000
18:163423:G:C	Q44H	1.000
18:163423:G:T	Q44H	1.000
18:163428:T:A	V46D	1.000
18:178954:G:A	G73R	1.000
18:178954:G:C	G73R	1.000
18:178954:G:T	G73W	1.000
18:178955:G:A	G73E	1.000
18:178999:T:C	F88L	1.000
18:179000:T:C	F88S	1.000
18:179000:T:G	F88C	1.000
18:179001:C:A	F88L	1.000
18:179001:C:G	F88L	1.000
18:180251:G:A	G106R	1.000
18:180251:G:C	G106R	1.000
18:180252:G:A	G106E	1.000
18:180255:T:C	L107S	1.000
18:180260:A:G	N109D	1.000
18:180262:C:A	N109K	1.000
18:180262:C:G	N109K	1.000
18:180264:T:C	L110P	1.000
18:180267:G:A	G111D	1.000
18:180267:G:T	G111V	1.000
18:180271:C:A	N112K	1.000
18:180271:C:G	N112K	1.000
18:180273:C:T	T113I	1.000

dbSNP variants (sampled 300 via entrez): RS1000019764 (18:190968 CA>C,CAA), RS1000031482 (18:157992 T>A,G), RS1000075097 (18:176915 G>T), RS1000124573 (18:208850 A>G), RS1000179329 (18:166074 T>G), RS1000218314 (18:209018 G>T), RS1000253347 (18:164277 A>G), RS1000296657 (18:180513 C>T), RS1000445356 (18:172575 G>A,T), RS1000698206 (18:166268 G>A), RS1000699209 (18:168643 C>A,T), RS1000784783 (18:205400 C>T), RS1000850929 (18:186856 T>C), RS1000865995 (18:197196 A>G,T), RS1000904993 (18:173817 A>C)

Disease associations

OMIM: gene MIM:607274 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic disease	Strong	Autosomal recessive
complex neurodevelopmental disorder	Moderate	Autosomal recessive

Mondo (2): syndromic disease (MONDO:0002254), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012490_546	Femur bone mineral density x serum urate levels interaction	5.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D013577	Syndrome	C23.550.288.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1293295 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C19: Ubiquitin-specific protease

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
VLX1570	Inhibition	5.82	pKd
IU1	Inhibition	5.33	pIC50

Binding affinities (BindingDB)

60 measured of 142 human assays (142 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-(7-azabicyclo[2.2.1]heptan-7-yl)-1-[1-(4-chlorophenyl)-2-methyl-6-(methylsulfonylmethyl)indol-3-yl]ethanone	IC50	75 nM	US-11560385: Proteasome activity enhancing compounds
1-[1-(4-chlorophenyl)-2-methyl-6-(oxetan-3-ylmethyl)indol-3-yl]-2-[(2S)-2-(hydroxymethyl)-7-azabicyclo[2.2.1]heptan-7-yl]ethanone	IC50	75 nM	US-11560385: Proteasome activity enhancing compounds
1-[1-(4-chlorophenyl)-2-methyl-6-(oxetan-3-ylmethyl)indol-3-yl]-2-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)ethanone	IC50	75 nM	US-11560385: Proteasome activity enhancing compounds
2-[3-[2-(7-azabicyclo[2.2.1]heptan-7-yl)acetyl]-1-(4-chlorophenyl)-2-methylindol-6-yl]acetonitrile	IC50	75 nM	US-11560385: Proteasome activity enhancing compounds
3-[1-(4-chlorophenyl)-3-[2-(3-hydroxy-3-propan-2-yl-8-azabicyclo[3.2.1]octan-8-yl)acetyl]-2-methylindol-6-yl]propanenitrile	IC50	75 nM	US-11560385: Proteasome activity enhancing compounds
4-[5-[(1R,2R)-2-(2-cyanoethyl)cyclopropyl]-3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[5-(4-cyanobut-1-ynyl)-2-methyl-3-[2-(2-oxa-6-azatricyclo[3.3.1.13,7]decan-6-yl)acetyl]pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methyl-5-(3-pyrazol-1-ylpropyl)pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-chloro-2-[(E)-4-cyano-4-methylpent-1-enyl]-4-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-5-methylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methyl-5-(2-trimethylsilylethyl)pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methyl-5-[2-(oxetan-3-yl)ethynyl]pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(1R,5R)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(1R,5R)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(2S)-2-methoxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(1R,5R)-3-hydroxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2,4,5-trimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-chloro-4-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-fluoro-4-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-(5-hydroxy-2-azatricyclo[3.3.1.13,7]decan-2-yl)acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(6R)-6-hydroxy-8-azabicyclo[3.2.1]octan-8-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[2,5-dimethyl-3-[2-(2-oxa-6-azatricyclo[3.3.1.13,7]decan-6-yl)acetyl]pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-(3-hydroxy-9-azabicyclo[3.3.1]nonan-9-yl)acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(1R,5R)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
3-fluoro-4-[3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[2,5-dimethyl-3-[2-[(5S,7S)-2-oxa-6-azatricyclo[3.3.1.03,7]nonan-6-yl]acetyl]pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
2,6-difluoro-4-[3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[5-chloro-3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[2,3-dichloro-4-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-5-methylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[5-cyclopropyl-3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-fluoro-2,5-dimethyl-4-[2-[(2S)-2-methyl-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[2,5-dimethyl-3-[2-[(2R,6S)-4-oxa-10-azatricyclo[5.2.1.02,6]decan-10-yl]acetyl]pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
2,5-difluoro-4-[3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methyl-5-(trifluoromethyl)pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[5-cyclopentyl-3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[5-cyclohexyl-3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methyl-5-propan-2-ylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[5-tert-butyl-3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[5-butan-2-yl-3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methyl-5-(2,2,2-trifluoroethyl)pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
2-fluoro-4-[3-fluoro-2,5-dimethyl-4-[2-(2-oxa-6-azatricyclo[3.3.1.13,7]decan-6-yl)acetyl]pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
1-[1-(4-chloro-3-fluorophenyl)-2,5-dimethylpyrrol-3-yl]-2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]ethanone	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[5-bromo-3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-fluoro-2,5-dimethyl-4-[2-[(2R)-2-methyl-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[2,5-dimethyl-3-[2-[(2R)-2-methyl-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(2S,3R)-2,3-dimethyl-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[2,5-dimethyl-3-[2-(1-methyl-7-azabicyclo[2.2.1]heptan-7-yl)acetyl]pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[4-bromo-3-[2-[(2S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2-methyl-5-[(2-methyl-1,3-thiazol-4-yl)methyl]pyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds
4-[3-[2-[(2S)-2-(hydroxymethyl)-7-azabicyclo[2.2.1]heptan-7-yl]acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	IC50	275 nM	US-11560385: Proteasome activity enhancing compounds

ChEMBL bioactivities

218 potent at pChembl≥5 of 222 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.12	IC50	75	nM	CHEMBL5894641
7.12	IC50	75	nM	CHEMBL5919941
7.12	IC50	75	nM	CHEMBL5876931
7.12	IC50	75	nM	CHEMBL5930961
7.12	IC50	75	nM	CHEMBL5838259
7.12	IC50	75	nM	CHEMBL5955553
7.12	IC50	75	nM	CHEMBL5932216
7.12	IC50	75	nM	CHEMBL6049993
6.56	IC50	275	nM	CHEMBL5768524
6.56	IC50	275	nM	CHEMBL6037734
6.56	IC50	275	nM	CHEMBL5915091
6.56	IC50	275	nM	CHEMBL6004050
6.56	IC50	275	nM	CHEMBL5918035
6.56	IC50	275	nM	CHEMBL5791407
6.56	IC50	275	nM	CHEMBL5925113
6.56	IC50	275	nM	CHEMBL5903518
6.56	IC50	275	nM	CHEMBL5867897
6.56	IC50	275	nM	CHEMBL5978136
6.56	IC50	275	nM	CHEMBL5873526
6.56	IC50	275	nM	CHEMBL5758905
6.56	IC50	275	nM	CHEMBL5775377
6.56	IC50	275	nM	CHEMBL5941163
6.56	IC50	275	nM	CHEMBL6013212
6.56	IC50	275	nM	CHEMBL5994938
6.56	IC50	275	nM	CHEMBL6024697
6.56	IC50	275	nM	CHEMBL5996802
6.56	IC50	275	nM	CHEMBL6013176
6.56	IC50	275	nM	CHEMBL5948729
6.56	IC50	275	nM	CHEMBL5979065
6.56	IC50	275	nM	CHEMBL6039129
6.56	IC50	275	nM	CHEMBL5825774
6.56	IC50	275	nM	CHEMBL5918337
6.56	IC50	275	nM	CHEMBL5892777
6.56	IC50	275	nM	CHEMBL5799144
6.56	IC50	275	nM	CHEMBL5990293
6.56	IC50	275	nM	CHEMBL6065924
6.56	IC50	275	nM	CHEMBL6032790
6.56	IC50	275	nM	CHEMBL6030667
6.56	IC50	275	nM	CHEMBL6006121
6.56	IC50	275	nM	CHEMBL5924197
6.56	IC50	275	nM	CHEMBL5863106
6.56	IC50	275	nM	CHEMBL5933440
6.56	IC50	275	nM	CHEMBL5832935
6.56	IC50	275	nM	CHEMBL6029856
6.56	IC50	275	nM	CHEMBL6038508
6.56	IC50	275	nM	CHEMBL6033106
6.56	IC50	275	nM	CHEMBL5924978
6.56	IC50	275	nM	CHEMBL5849950
6.56	IC50	275	nM	CHEMBL5989560
6.56	IC50	275	nM	CHEMBL6027743

PubChem BioAssay actives

4 with measured affinity, of 37 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
1-[1-(4-fluorophenyl)-2,5-dimethylpyrrol-3-yl]-2-piperidin-1-ylethanone	1930816: Inhibition of human USP14 using Ub-PA as substrate assessed as deubiquitination level incubated for 1 hr by SDS-PAGE assay	ic50	0.6800	uM
4-[3-[2-(4-hydroxypiperidin-1-yl)acetyl]-2,5-dimethylpyrrol-1-yl]benzonitrile	1930816: Inhibition of human USP14 using Ub-PA as substrate assessed as deubiquitination level incubated for 1 hr by SDS-PAGE assay	ic50	0.8300	uM
1-[1-(4-fluorophenyl)-2,5-dimethylpyrrol-3-yl]-2-pyrrolidin-1-ylethanone	1195681: Inhibition of USP14 (unknown origin) by Ub-AMC assay	ic50	4.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
cobaltous chloride	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cyclosporine	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
beta-methylcholine	affects expression	1
phenethyl isothiocyanate	affects binding	1
CGP 52608	affects binding, increases reaction	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
bisphenol B	increases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Vehicle Emissions	affects expression, increases reaction	1
Benztropine	increases expression	1
Chenodeoxycholic Acid	affects cotreatment, increases expression	1
Cisplatin	decreases expression	1
Deoxycholic Acid	affects cotreatment, increases expression	1
Diacetyl	increases expression	1
Doxorubicin	decreases expression	1
Fluorouracil	decreases expression	1
Formaldehyde	decreases expression	1
Glycochenodeoxycholic Acid	increases expression, affects cotreatment	1
Glycocholic Acid	affects cotreatment, increases expression	1
Glycodeoxycholic Acid	affects cotreatment, increases expression	1

ChEMBL screening assays

27 unique, capped per target: 24 binding, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614424	Functional	PUBCHEM_BIOASSAY: Small-molecule inhibitor of deubiquitinating enzyme USP14. (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL2411909	Binding	Inhibition of human USP14	Vialinin A is a ubiquitin-specific peptidase inhibitor. — Bioorg Med Chem Lett

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2KI	Abcam HeLa USP14 KO	Cancer cell line	Female
CVCL_KU17	HeLa SilenciX USP14	Cancer cell line	Female
CVCL_TW56	HAP1 USP14 (-) 1	Cancer cell line	Male
CVCL_TW57	HAP1 USP14 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00027456	PHASE2	COMPLETED	Leptin to Treat Severe Insulin Resistance - Pilot Study
NCT00213447	Not specified	COMPLETED	T Cell Response in Hypersensitivity Syndrome
NCT02240888	Not specified	COMPLETED	Vaccination in Inflammatory Rheumatic Disease (VACCIMIL). The Impact of Antirheumatic Treatment on Antibody Response
NCT02526082	Not specified	ACTIVE_NOT_RECRUITING	Long-term Follow-up of the Helsinki Businessmen Study
NCT02637518	Not specified	UNKNOWN	Comprehensive Validation of Frailty Assessment Tools in Older Adults in Different Clinical and Social Settings
NCT02971072	Not specified	COMPLETED	Neurophysiology of Weakness and Exercise in Rotator Cuff Tendinopathy
NCT02974569	Not specified	COMPLETED	Improving Symptom Self-management in Adolescents & Young Adults With Cancer
NCT03265561	Not specified	COMPLETED	Spinal Infection Management With Structural Allograft
NCT04190342	Not specified	COMPLETED	Effects of a Traditional Chinese Exercise Program on Symptom Cluster in Breast Cancer Patients
NCT04874584	Not specified	COMPLETED	Culturally Tailored Nurse Coaching Study for Cancer Symptom Management
NCT04909489	Not specified	UNKNOWN	PDR and SKYD of Dyslipidemia’s Characteristics From the Oxidative Stress Enhancement Caused by Inhibition of Serine Metabolic Pathway
NCT05218122	Not specified	UNKNOWN	Characteristics of LKDS and PBSS of KOA Based on the Enhancement of Inflammatory Response by TGF-β/Smad Pathway Inhibited
NCT05266118	Not specified	COMPLETED	Patient Reported Symptoms the First Week After Intensive Care Unit Discharge and up to Hospital Discharge
NCT05321966	Not specified	COMPLETED	The Effect of Video Training on Symptom Burden Patients Undergoing Hemodialysis Treatment
NCT05818748	Not specified	UNKNOWN	Effect Of Virtual Reality Distraction on Symptom Control and Anxiety in Children With Leukemia
NCT05837988	Not specified	UNKNOWN	Construction of Symptom Network in Maintenance Hemodialysis Patients
NCT06143436	Not specified	UNKNOWN	TCM Constitution, Pattern Types, and Disease Factors in Primary Lung Cancer.
NCT06222008	Not specified	UNKNOWN	Study on Symptom Clusters During Chemotherapy in Ovarian Cancer Patients With Different Chinese Medicine Constitution
NCT06412107	Not specified	COMPLETED	Somatic Acupressure for Symptom Cluster Management in Breast Cancer Survivors
NCT06847360	Not specified	RECRUITING	Home-based Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) for IBS Pain
NCT07281300	Not specified	RECRUITING	Mindfulness-Oriented Respiratory Distress Symptom Intervention for Lung Cancer
NCT07315672	Not specified	RECRUITING	Acupressure for Cough in Lung Cancer Survivors
NCT07479654	Not specified	NOT_YET_RECRUITING	AI-Enabled Frailty Risk Prediction in Adult Congenital Heart Disease
NCT07495358	Not specified	NOT_YET_RECRUITING	Development and Usability Evaluation of a Knowledge Graph-Based Symptom Management System for Patients With Breast Cancer Undergoing Chemotherapy
NCT07576114	Not specified	RECRUITING	Comparison of Gluteal Muscle Activation and Core Strengthening in Dead Butt Syndrome Syndrome
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder