OTUD7B

Summary

OTUD7B (OTU deubiquitinase 7B, HGNC:16683) is a protein-coding gene on chromosome 1q21.2, encoding OTU domain-containing protein 7B (Q6GQQ9). Negative regulator of the non-canonical NF-kappa-B pathway that acts by mediating deubiquitination of TRAF3, an inhibitor of the NF-kappa-B pathway, thereby acting as a negative regulator of B-cell responses.

Enables K48-linked deubiquitinase activity and cysteine-type deubiquitinase activity. Involved in several processes, including negative regulation of protein localization to nucleus; protein deubiquitination; and regulation of intracellular signal transduction. Located in cytoplasm and nucleus.

Source: NCBI Gene 56957 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 142 total
• Druggable target: yes
• MANE Select transcript: NM_020205

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16683
Approved symbol	OTUD7B
Name	OTU deubiquitinase 7B
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Aliases	CEZANNE
Ensembl gene	ENSG00000264522
Ensembl biotype	protein_coding
OMIM	611748
Entrez	56957

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 retained_intron

ENST00000417191, ENST00000581312, ENST00000619871, ENST00000907908, ENST00000907909, ENST00000907910, ENST00000907911, ENST00000907912, ENST00000907913

RefSeq mRNA: 1 — MANE Select: NM_020205 NM_020205

CCDS: CCDS72903

Canonical transcript exons

ENST00000581312 — 12 exons

Exon	Start	End
ENSE00002267252	150010448	150010726
ENSE00002699694	149977426	149977576
ENSE00002701922	149967294	149967521
ENSE00002706389	149971063	149971251
ENSE00002708252	149964222	149964349
ENSE00002715764	149965777	149965878
ENSE00002724857	149937812	149945065
ENSE00002725784	149947251	149947335
ENSE00003739590	149949629	149949778
ENSE00003740601	149950094	149950221
ENSE00003741388	149948969	149949083
ENSE00003742597	149959684	149959796

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 94.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.0019 / max 198.1038, expressed in 1737 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14287	15.9435	1730
14286	1.0984	473
14285	0.4451	190
14284	0.4348	220
14283	0.0801	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	94.91	gold quality
medial globus pallidus	UBERON:0002477	92.70	gold quality
sural nerve	UBERON:0015488	91.37	gold quality
globus pallidus	UBERON:0001875	91.31	gold quality
secondary oocyte	CL:0000655	90.38	gold quality
tendon of biceps brachii	UBERON:0008188	89.38	gold quality
corpus callosum	UBERON:0002336	88.24	gold quality
inferior vagus X ganglion	UBERON:0005363	87.75	gold quality
cerebellar vermis	UBERON:0004720	86.77	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.76	gold quality
spinal cord	UBERON:0002240	86.22	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	85.90	gold quality
tendon	UBERON:0000043	85.86	gold quality
biceps brachii	UBERON:0001507	85.85	gold quality
tibial nerve	UBERON:0001323	85.49	gold quality
colonic epithelium	UBERON:0000397	85.38	gold quality
muscle of leg	UBERON:0001383	84.84	gold quality
gastrocnemius	UBERON:0001388	84.79	gold quality
subthalamic nucleus	UBERON:0001906	84.25	gold quality
stromal cell of endometrium	CL:0002255	84.03	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.93	gold quality
lateral globus pallidus	UBERON:0002476	83.66	gold quality
calcaneal tendon	UBERON:0003701	83.59	gold quality
oocyte	CL:0000023	83.30	gold quality
sperm	CL:0000019	83.14	gold quality
nipple	UBERON:0002030	82.89	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	82.38	gold quality
muscle organ	UBERON:0001630	82.14	gold quality
tibia	UBERON:0000979	82.03	gold quality
islet of Langerhans	UBERON:0000006	81.69	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.20
E-MTAB-6058	no	271.01
E-ENAD-17	no	135.42
E-MTAB-6142	no	36.81

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CXCL8	Repression
ICAM1	Repression

miRNA regulators (miRDB)

218 targeting OTUD7B, 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-9-5P	100.00	72.28	2361
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753

Literature-anchored findings (GeneRIF, showing 28)

• cleaves ubiquitin from proteins (PMID:12682062)
• Cezanne forms a novel negative feedback loop in pro-inflammatory signaling and that it suppresses NF-kappaB activation by targeting RIP1 signaling intermediaries for deubiquitination (PMID:18178551)
• H(2)O(2) prolongs NF-kappaB activation in co-stimulated cells by suppressing the negative regulatory functions of Cezanne and IkappaBalpha. (PMID:18474597)
• Cezanne is identified as the first deubiquitinase with Lys11-linkage preference. (PMID:20622874)
• DJ-1 enhances cell survival through the binding of Cezanne, a negative regulator of NF-kappaB. (PMID:21097510)
• There is an excessive inflammatory response but insufficient up-regulation of A20 expression in inflammatory bowel disease patients. (PMID:21624200)
• identified a deubiquitinating enzyme, Cezanne-1, that opposes receptor degradation and enhances EGFR signaling (PMID:22179831)
• Inflammatory responses to ischemia are controlled by a balance between TRAF6 ubiquitination and deubiquitination, and Cezanne is a key regulator of this process. (PMID:23564640)
• Genome wide association study shows evidence of association between mammographic density and SNPs in high linkage disequilibrium with rs11205277, rs11205303 in gene MTMR11 and rs67807996 in gene OTUD7B. (PMID:25353672)
• data suggest that Cezanne is essential for HIF-1alpha protein stability and that loss of Cezanne stimulates HIF-1alpha degradation via proteasome-independent routes, possibly through chaperone-mediated autophagy. (PMID:25355043)
• Cezanne has a pivotal role in tumor progression and prognosis, and may act as a potential prognostic biomarker for survival in hepatocellular carcinoma patients. (PMID:25638165)
• Taken together, these results suggest that hepatitis C virus NS5A protein interacts with OTUD7B, thereby modulating its deubiquitinase activity. (PMID:26112491)
• these data reveal a novel mechanism for the regulation of the expression of HIF2a, demonstrating that the HIF2a promoter is regulated by E2F1 directly and that Cezanne regulates HIF2a expression through control of E2F1 levels (PMID:26148512)
• expression of OTUD7B and NIK were negatively correlated in non-small cell lung cancer tumor samples. The higher expression of OTUD7B was associated with smaller tumor size, less lymph node metastasis and earlier TNM stage. the high expression of OTUD7B was associated with good prognosis of NSCLC patients, and a high OTUD7B/low NIK index can predict even better prognosis. also, OTUD7B is an independent markers of survival. (PMID:27499151)
• crystal structures of Cezanne alone and in complex with monoubiquitin and Lys11-linked diubiquitin, in combination with hydrogen-deuterium exchange mass spectrometry, enable a reconstruction of the enzymatic cycle in great detail (PMID:27732584)
• Findings indicated both cezanne-1 and IGF1R expressions were negative independent predictive factors for the prognosis of lung adenocarcinoma, respectively. There was a close positive interrelationship between cezanne-1 and IGF1R expression. (PMID:28365890)
• TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling (PMID:28489822)
• Study demonstrated that the N-terminal UBA domain is crucial for the function of Cezanne during NF-kappaB activation. Cezanne is recognized and recruited into activated TNFR complex by specifically binding to polyubiquitinated signaling proteins after TNF stimulation through its N-terminal polyubiquitin binding site. (PMID:28817177)
• Cezanne may be a novel antioncogene that has a pivotal role in the invasion of hepatocellular carcinoma and contribute to the selection of patients who may benefit from adjuvant transcatheter arterial chemoembolization to prevent recurrence. (PMID:28880268)
• Cezanne binds established APC/C substrates and reverses their APC/C-mediated ubiquitination. Cezanne depletion accelerates APC/C substrate degradation and causes errors in mitotic progression and formation of micronuclei. (PMID:29973362)
• Cezanne serves as a “reader” of the Lys63-linkage polyubiquitin at DNA damage sites and an “eraser” of the Lys11-linkage ubiquitination, indicating a crosstalk between linkage-specific ubiquitination at DNA damage sites (PMID:31699778)
• The present study demonstrates that linc00976 enhances the proliferation and invasion ability of PC cells by upregulating OTUD7B expression, which was a target of miR-137. Ultimately, OTUD7B mediates EGFR and MAPK signaling pathway. (PMID:31747939)
• Oxygen-dependent asparagine hydroxylation of the ubiquitin-associated (UBA) domain in Cezanne regulates ubiquitin binding. (PMID:31937588)
• Cezanne is a critical regulator of pathological arterial remodelling by targeting beta-catenin signalling. (PMID:33599243)
• OTUD7B stabilizes estrogen receptor alpha and promotes breast cancer cell proliferation. (PMID:34035221)
• OTUD7B deubiquitinates and stabilizes YAP1 to upregulate NUAK2 expression, thus accelerating gastric cancer procession. (PMID:37429790)
• The deubiquitinating enzyme OTUD7b protects dendritic cells from TNF-induced apoptosis by stabilizing the E3 ligase TRAF2. (PMID:37516734)
• OTU deubiquitinase 7B facilitates the hyperthermia-induced inhibition of lung cancer progression through enhancing Smac-mediated mitochondrial dysfunction. (PMID:38088504)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	otud7b	ENSDARG00000017220
mus_musculus	Otud7b	ENSMUSG00000038495
rattus_norvegicus	Otud7b	ENSRNOG00000042068

Paralogs (2): TNFAIP3 (ENSG00000118503), OTUD7A (ENSG00000169918)

Protein

Protein identifiers

OTU domain-containing protein 7B — Q6GQQ9 (reviewed: Q6GQQ9)

Alternative names: Cellular zinc finger anti-NF-kappa-B protein, Zinc finger A20 domain-containing protein 1, Zinc finger protein Cezanne

All UniProt accessions (2): Q6GQQ9, Q5SZ59

UniProt curated annotations — full annotation on UniProt →

Function. Negative regulator of the non-canonical NF-kappa-B pathway that acts by mediating deubiquitination of TRAF3, an inhibitor of the NF-kappa-B pathway, thereby acting as a negative regulator of B-cell responses. In response to non-canonical NF-kappa-B stimuli, deubiquitinates ‘Lys-48’-linked polyubiquitin chains of TRAF3, preventing TRAF3 proteolysis and over-activation of non-canonical NF-kappa-B. Negatively regulates mucosal immunity against infections. Deubiquitinates ZAP70, and thereby regulates T cell receptor (TCR) signaling that leads to the activation of NF-kappa-B. Plays a role in T cell homeostasis and is required for normal T cell responses, including production of IFNG and IL2. Mediates deubiquitination of EGFR. Has deubiquitinating activity toward ‘Lys-11’, ‘Lys-48’ and ‘Lys-63’-linked polyubiquitin chains. Has a much higher catalytic rate with ‘Lys-11’-linked polyubiquitin chains (in vitro); however the physiological significance of these data are unsure. Hydrolyzes both linear and branched forms of polyubiquitin. Acts as a regulator of mTORC1 and mTORC2 assembly by mediating ‘Lys-63’-linked deubiquitination of MLST8, thereby promoting assembly of the mTORC2 complex, while inhibiting formation of the mTORC1 complex.

Subunit / interactions. Interacts with ZAP70 in activated T cells, but not in resting T cells. Interacts with TRAF3. Interacts with TRAF6. Interacts with PARK7, leading to inhibit deubiquitinase activity. Interacts with EGFR, ITCH and NEDD4.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed. Abundant in kidney, heart and fetal liver. Expressed differentially among B-cells at distinct developmental stages. Higher expression seen in primary immature B-cells as compared to the mature cells.

Post-translational modifications. Phosphorylated by EGFR.

Activity regulation. Deubiquitinase activity is inhibited following interaction with PARK7.

Domain organisation. The protein undergoes a significant conformation change upon binding to ubiquitinated substrates. The loop that precedes the active site is in an autoinhibitory conformation in the apoprotein. Ubiquitin binding leads to a conformation change; the loop is stabilized in a catalytically competent conformation with the result that the active site Cys can form the reaction state intermediate.

Induction. By TNF.

Similarity. Belongs to the peptidase C64 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6GQQ9-1	1	yes
Q6GQQ9-2	2

RefSeq proteins (1): NP_064590* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002653	Znf_A20	Domain
IPR003323	OTU_dom	Domain
IPR051346	OTU_Deubiquitinase	Family

Pfam: PF01754, PF02338

UniProt features (77 total): mutagenesis site 14, strand 14, helix 14, region of interest 7, compositionally biased region 5, modified residue 5, binding site 4, active site 3, sequence conflict 3, turn 2, chain 1, domain 1, short sequence motif 1, zinc finger region 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5LRW	X-RAY DIFFRACTION	2
5LRU	X-RAY DIFFRACTION	2.2
5LRV	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6GQQ9-F1	67.63	0.35

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): 191; 194 (nucleophile); 358 (proton acceptor); 197 (stabilizes the conformation of the regulatory loop)

Ligand- & substrate-binding residues (4): 802; 807; 819; 822

Post-translational modifications (5): 100, 464, 467, 471, 729

Mutagenesis-validated functional residues (14):

Position	Phenotype
155–156	reduces deubiquitinating activity.
157	reduces deubiquitinating activity with ’lys-11’-linked ubiquitin chains; no effect on cleavage of ’lys-48’-linked and ’l
193	loss of deubiquitinating activity due to stabilization of the autoinhibited conformation.
194	loss of deubiquitinating activity. increased ability to interact with polyubiquitin.
194	loss of deubiquitinating activity.
194	loss of deubiquitinating activity; when associated with n-358.
197	strongly reduces deubiquitinating activity.
197	reduces deubiquitinating activity.
210	reduces deubiquitinating activity.
295	loss of deubiquitinating activity.
358	loss of deubiquitinating activity.
358	loss of deubiquitinating activity; when associated with s-194.
809	does not affect interaction with egfr.
810	impairs interaction with egfr.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5357786	TNFR1-induced proapoptotic signaling
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-5357956	TNFR1-induced NF-kappa-B signaling pathway
R-HSA-5689896	Ovarian tumor domain proteases

MSigDB gene sets: 260 (showing top): E2F_Q4, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, FREAC2_01, E2F4DP1_01, NKX25_02, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, MAZ_Q6, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, FOXO4_01, FOXO1_01, GGGTGGRR_PAX4_03, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_ORGAN_OR_TISSUE_SPECIFIC_IMMUNE_RESPONSE

GO Biological Process (18): negative regulation of transcription by RNA polymerase II (GO:0000122), in utero embryonic development (GO:0001701), adaptive immune response (GO:0002250), mucosal immune response (GO:0002385), protein deubiquitination (GO:0016579), negative regulation of interleukin-8 production (GO:0032717), protein K11-linked deubiquitination (GO:0035871), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), protein K63-linked deubiquitination (GO:0070536), protein K48-linked deubiquitination (GO:0071108), protein deubiquitination involved in ubiquitin-dependent protein catabolic process (GO:0071947), negative regulation of protein localization to nucleus (GO:1900181), negative regulation of TORC1 signaling (GO:1904262), positive regulation of TORC2 signaling (GO:1904515), immune system process (GO:0002376), proteolysis (GO:0006508), TORC1 signaling (GO:0038202), TORC2 signaling (GO:0038203)

GO Molecular Function (10): DNA binding (GO:0003677), cysteine-type deubiquitinase activity (GO:0004843), cysteine-type peptidase activity (GO:0008234), zinc ion binding (GO:0008270), K63-linked polyubiquitin modification-dependent protein binding (GO:0070530), K48-linked deubiquitinase activity (GO:1990380), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TNF signaling	3
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein deubiquitination	4
TOR signaling	2
deubiquitinase activity	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
chordate embryonic development	1
immune response	1
organ or tissue specific immune response	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
negative regulation of cytokine production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
ubiquitin-dependent protein catabolic process	1
protein localization to nucleus	1
regulation of protein localization to nucleus	1
negative regulation of protein localization	1
negative regulation of TOR signaling	1
TORC1 signaling	1
regulation of TORC1 signaling	1
positive regulation of TOR signaling	1
TORC2 signaling	1
regulation of TORC2 signaling	1
biological_process	1
protein metabolic process	1
nucleic acid binding	1
cysteine-type peptidase activity	1
peptidase activity	1
transition metal ion binding	1
polyubiquitin modification-dependent protein binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

1084 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTUD7B	WIPI1	Q5MNZ9	962
OTUD7B	WIPI2	Q9Y4P8	864
OTUD7B	WDR45B	Q5MNZ6	853
OTUD7B	PARK7	Q99497	849
OTUD7B	WDR45	Q9Y484	849
OTUD7B	ZUP1	Q96AP4	717
OTUD7B	OTUB1	Q96FW1	713
OTUD7B	TRAF3	Q13114	709
OTUD7B	OTUD3	Q5T2D3	692
OTUD7B	OTULIN	Q96BN8	673
OTUD7B	CYLD	Q9NQC7	669
OTUD7B	TRAF6	Q9Y4K3	663
OTUD7B	OTUD5	Q96G74	652
OTUD7B	USP15	Q9Y4E8	625
OTUD7B	STAMBP	O95630	611

IntAct

57 interactions, top by confidence:

A	B	Type	Score
HIF1AN	GMDS	psi-mi:“MI:0914”(association)	0.640
OTUD7B	CCDC50	psi-mi:“MI:0915”(physical association)	0.630
OTUD7B	CCDC50	psi-mi:“MI:0403”(colocalization)	0.630
OTUD7B	PIK3R3	psi-mi:“MI:0915”(physical association)	0.570
PIK3R3	OTUD7B	psi-mi:“MI:0915”(physical association)	0.570
OTUD7B	EPM2AIP1	psi-mi:“MI:0915”(physical association)	0.560
OTUD7B	OTULIN	psi-mi:“MI:0915”(physical association)	0.560
OTUD7B	SPART	psi-mi:“MI:0915”(physical association)	0.560
DAZAP2	OTUD7B	psi-mi:“MI:0915”(physical association)	0.560
OTUD7B	HSFY1	psi-mi:“MI:0915”(physical association)	0.560
PSMB1	OTUD7B	psi-mi:“MI:0915”(physical association)	0.560
OTUD7B	SAXO4	psi-mi:“MI:0915”(physical association)	0.560
OTUD7B	CDIP1	psi-mi:“MI:0915”(physical association)	0.560
TNIP2	OTUD7B	psi-mi:“MI:0915”(physical association)	0.550
TNFRSF10A	TNFRSF10B	psi-mi:“MI:0914”(association)	0.530
PARK7	OTUD7B	psi-mi:“MI:0915”(physical association)	0.520
OTUD7B	Traf3	psi-mi:“MI:0915”(physical association)	0.400
Ltbr	OTUD7B	psi-mi:“MI:0915”(physical association)	0.400
CASP8	OTUD7B	psi-mi:“MI:0915”(physical association)	0.400
OTUD7B	TRAF6	psi-mi:“MI:0915”(physical association)	0.400
YWHAB	OTUD7B	psi-mi:“MI:0915”(physical association)	0.370
OTUD7B	ZDHHC17	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (135): OTUD7B (Two-hybrid), OTUD7B (Two-hybrid), PIK3R3 (Affinity Capture-Luminescence), UBC (Biochemical Activity), OTUD7B (Affinity Capture-Western), UBC (Biochemical Activity), OTUD7B (Affinity Capture-RNA), AURKA (Biochemical Activity), UBC (Biochemical Activity), UBC (Co-crystal Structure), UBC (Reconstituted Complex), OTUD7B (Affinity Capture-MS), OTUD7B (Affinity Capture-MS), OTUD7B (Reconstituted Complex), OTUD7B (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IXF6, A1L2G3, A2VDM8, B0W2R4, C4A0D9, D3ZHS6, E6ZGB4, O75151, P0C090, P0CH95, Q08BR4, Q1LUC3, Q24574, Q28C33, Q2V2M9, Q4VGL6, Q52L14, Q56R14, Q5F363, Q5F3N6, Q5JSH3, Q5TC82, Q5XJV7, Q62315, Q66JB6, Q6GQQ9, Q6INA9, Q6NUC6, Q6P949, Q6PDG5, Q80TJ7, Q8BLB8, Q8K2L8, Q8QG78, Q8TAQ2, Q91YE9, Q92560, Q92830, Q92831, Q92833

Diamond homologs: A0JMQ9, A6QP16, B1H2Q2, B2RUR8, P21580, Q4R8W3, Q5U595, Q60769, Q6GQQ9, Q6NUB7, Q7M760, Q8R554, Q8TE49, Q9UGI0, Q9VH90

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
OTUD7B	“down-regulates activity”	RIPK1	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 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.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of canonical NF-kappaB signal transduction	6	14.1×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	120
Likely benign	4
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

1950 predictions. Top by Δscore:

Variant	Effect	Δscore
1:149945061:GGAGC:G	acceptor_gain	1.0000
1:149945063:AGCC:A	acceptor_loss	1.0000
1:149945064:GC:G	acceptor_gain	1.0000
1:149945064:GCC:G	acceptor_loss	1.0000
1:149945065:CC:C	acceptor_gain	1.0000
1:149945066:CTGGA:C	acceptor_loss	1.0000
1:149945067:T:A	acceptor_loss	1.0000
1:149947331:TTACA:T	acceptor_gain	1.0000
1:149947332:TACA:T	acceptor_gain	1.0000
1:149947334:CA:C	acceptor_gain	1.0000
1:149947334:CACTA:C	acceptor_gain	1.0000
1:149947336:C:CC	acceptor_gain	1.0000
1:149947338:A:C	acceptor_gain	1.0000
1:149948963:GCTTA:G	donor_loss	1.0000
1:149948964:CTTAC:C	donor_loss	1.0000
1:149948965:TTA:T	donor_loss	1.0000
1:149948966:TACC:T	donor_loss	1.0000
1:149948967:A:AT	donor_loss	1.0000
1:149949079:CACAG:C	acceptor_gain	1.0000
1:149949080:ACAG:A	acceptor_gain	1.0000
1:149949081:CAG:C	acceptor_gain	1.0000
1:149949081:CAGC:C	acceptor_gain	1.0000
1:149949084:C:CC	acceptor_gain	1.0000
1:149950089:CTCA:C	donor_loss	1.0000
1:149950090:TCA:T	donor_loss	1.0000
1:149950091:CACCT:C	donor_loss	1.0000
1:149950092:A:C	donor_loss	1.0000
1:149950093:CCTT:C	donor_gain	1.0000
1:149950220:CC:C	acceptor_gain	1.0000
1:149950221:CC:C	acceptor_gain	1.0000

AlphaMissense

5506 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:149943934:A:G	C819R	1.000
1:149943970:A:G	C807R	1.000
1:149943984:C:G	C802S	1.000
1:149943985:A:G	C802R	1.000
1:149943985:A:T	C802S	1.000
1:149949034:A:C	F391L	1.000
1:149949034:A:T	F391L	1.000
1:149949036:A:G	F391L	1.000
1:149949667:A:G	L362P	1.000
1:149949667:A:T	L362H	1.000
1:149949675:A:C	F359L	1.000
1:149949675:A:T	F359L	1.000
1:149949676:A:C	F359C	1.000
1:149949676:A:G	F359S	1.000
1:149949677:A:C	F359V	1.000
1:149949677:A:G	F359L	1.000
1:149949677:A:T	F359I	1.000
1:149949678:G:C	H358Q	1.000
1:149949678:G:T	H358Q	1.000
1:149949680:G:C	H358D	1.000
1:149949692:A:C	Y354D	1.000
1:149949692:A:G	Y354H	1.000
1:149949694:G:T	A353D	1.000
1:149949697:A:G	L352P	1.000
1:149949697:A:T	L352H	1.000
1:149949703:A:G	L350P	1.000
1:149949749:A:C	Y335D	1.000
1:149949754:C:T	G333E	1.000
1:149949772:G:T	A327D	1.000
1:149950114:A:G	L318P	1.000

dbSNP variants (sampled 300 via entrez): RS1000089305 (1:150001569 C>A), RS1000167033 (1:149994737 A>C,G), RS1000198627 (1:149994326 T>C), RS1000220341 (1:149942544 T>C), RS1000275667 (1:150042713 T>G), RS1000339281 (1:149979180 T>C,G), RS1000351252 (1:150028975 G>A,T), RS1000375756 (1:149986638 C>G), RS1000397961 (1:150037130 G>A), RS1000407984 (1:150036814 C>A,G,T), RS1000480420 (1:149985919 T>A,G), RS1000602507 (1:149979837 C>A), RS1000627954 (1:150043250 C>A,G,T), RS1000650537 (1:149963515 G>C,T), RS1000677090 (1:149942325 T>A)

Disease associations

OMIM: gene MIM:611748 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST001762_228	Obesity-related traits	4.000000e-06
GCST002539_32	Schizophrenia	4.000000e-10
GCST002647_90	Height	4.000000e-19
GCST004988_217	Breast cancer	9.000000e-14
GCST006803_67	Schizophrenia	7.000000e-10
GCST006979_953	Heel bone mineral density	4.000000e-20
GCST007294_101	Body fat distribution (trunk fat ratio)	2.000000e-87
GCST007294_115	Body fat distribution (trunk fat ratio)	3.000000e-22
GCST007294_154	Body fat distribution (trunk fat ratio)	4.000000e-99
GCST007295_122	Body fat distribution (leg fat ratio)	1.000000e-76
GCST007295_14	Body fat distribution (leg fat ratio)	4.000000e-23
GCST007295_98	Body fat distribution (leg fat ratio)	5.000000e-92
GCST008103_32	Bipolar disorder	5.000000e-08
GCST009600_143	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	2.000000e-12
GCST010002_366	Refractive error	3.000000e-15
GCST010173_84	Triglyceride levels	7.000000e-10
GCST012226_576	Waist circumference adjusted for body mass index	2.000000e-09
GCST90013405_63	Liver enzyme levels (alanine transaminase)	6.000000e-16
GCST90020028_615	Hip circumference adjusted for BMI	3.000000e-09
GCST90020028_618	Hip circumference adjusted for BMI	2.000000e-08
GCST90020028_619	Hip circumference adjusted for BMI	6.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement
EFO:0009270	heel bone mineral density
EFO:0004341	body fat distribution
EFO:0004530	triglyceride measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630838 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

17 measured of 21 human assays (21 total across all organisms); most potent 17 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-cyano-3-fluoro-N-[5-(1H-indazol-4-yl)-1,3-thiazol-2-yl]pyrrolidine-3-carboxamide	IC50	550 nM	US-10590075: Cyanopyrrolidine derivatives as inhibitors for DUBs
(3R)-1-cyano-3-fluoro-N-[5-(1H-indazol-4-yl)-1,3-thiazol-2-yl]pyrrolidine-3-carboxamide	IC50	550 nM	US-10590075: Cyanopyrrolidine derivatives as inhibitors for DUBs
1-cyano-3-fluoro-N-[6-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-yl]pyrrolidine-3-carboxamide	IC50	550 nM	US-10590075: Cyanopyrrolidine derivatives as inhibitors for DUBs
7-(3-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-6-yl)-2-oxospiro[1,4-dihydroquinoline-3,3’-pyrrolidine]-1’-carbonitrile	IC50	550 nM	US-10654853: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors
7-(5-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-4-yl)-2-oxospiro[1,4-dihydroquinoline-3,3’-pyrrolidine]-1’-carbonitrile	IC50	550 nM	US-10654853: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors
6-(2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-6-yl)-2-oxospiro[1,4-dihydroquinoline-3,3’-pyrrolidine]-1’-carbonitrile	IC50	550 nM	US-10654853: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors
6-(5-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-4-yl)-2-oxospiro[1,4-dihydroquinoline-3,3’-pyrrolidine]-1’-carbonitrile	IC50	550 nM	US-10654853: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors
6-(3,5-dimethylpyrazolidin-4-yl)-2-oxospiro[1,4-dihydroquinoline-3,3’-pyrrolidine]-1’-carbonitrile	IC50	550 nM	US-10654853: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors
6-(3-methylpyrazolidin-4-yl)-2-oxospiro[1,4-dihydroquinoline-3,3’-pyrrolidine]-1’-carbonitrile	IC50	550 nM	US-10654853: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors
(3R)-7-(5-methyl-1H-indazol-4-yl)-2-oxospiro[1,4-dihydroquinoline-3,3’-pyrrolidine]-1’-carbonitrile	IC50	550 nM	US-10654853: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors
7-(1H-indazol-4-yl)-2-oxospiro[1,4-dihydroquinoline-3,3’-pyrrolidine]-1’-carbonitrile	IC50	550 nM	US-10654853: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors
6-(1H-indazol-4-yl)-2-oxospiro[1,4-dihydroquinoline-3,3’-pyrrolidine]-1’-carbonitrile	IC50	550 nM	US-10654853: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors
6-(1H-indazol-4-yl)-2-oxospiro[1H-pyrido[2,3-b][1,4]oxazine-3,3’-pyrrolidine]-1’-carbonitrile	IC50	550 nM	US-10654853: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors
7’-(3-Methyl-1H-indazol-6-yl)- 2’-oxo-1’,4’-dihydro-2’H- spiro┌pyrrolidine-3,3’- quinoline┐-1-carbonitrile	IC50	550 nM	US-11236092: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors
1-cyano-3-fluoro-N-[6-(1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]pyrrolidine-3-carboxamide	IC50	5500 nM	US-10590075: Cyanopyrrolidine derivatives as inhibitors for DUBs
7-(3-methylpyrazolidin-4-yl)-2-oxospiro[1,4-dihydroquinoline-3,3’-pyrrolidine]-1’-carbonitrile	IC50	5500 nM	US-10654853: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors
7-(3,5-dimethylpyrazolidin-4-yl)-2-oxospiro[1,4-dihydroquinoline-3,3’-pyrrolidine]-1’-carbonitrile	IC50	5500 nM	US-10654853: Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (DUB) inhibitors

ChEMBL bioactivities

302 potent at pChembl≥5 of 302 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.26	IC50	550	nM	CHEMBL5955500
6.26	IC50	550	nM	CHEMBL6014354
6.26	IC50	550	nM	CHEMBL5839972
6.26	IC50	550	nM	CHEMBL5872815
6.26	IC50	550	nM	CHEMBL5779379
6.26	IC50	550	nM	CHEMBL5981279
6.26	IC50	550	nM	CHEMBL6042144
6.26	IC50	550	nM	CHEMBL5747667
6.26	IC50	550	nM	CHEMBL5792201
6.26	IC50	550	nM	CHEMBL5975382
6.26	IC50	550	nM	CHEMBL6039142
6.26	IC50	550	nM	CHEMBL6034891
6.26	IC50	550	nM	CHEMBL5888520
6.26	IC50	550	nM	CHEMBL5862413
6.26	IC50	550	nM	CHEMBL5974259
6.26	IC50	550	nM	CHEMBL5818135
6.26	IC50	550	nM	CHEMBL6042571
6.26	IC50	550	nM	CHEMBL5964496
6.26	IC50	550	nM	CHEMBL5894349
6.26	IC50	550	nM	CHEMBL5870096
6.26	IC50	550	nM	CHEMBL5951890
6.26	IC50	550	nM	CHEMBL6058972
6.26	IC50	550	nM	CHEMBL5798841
6.26	IC50	550	nM	CHEMBL5936027
6.26	IC50	550	nM	CHEMBL5948305
6.26	IC50	550	nM	CHEMBL5790032
6.26	IC50	550	nM	CHEMBL5910905
6.26	IC50	550	nM	CHEMBL6047628
6.26	IC50	550	nM	CHEMBL5925066
6.26	IC50	550	nM	CHEMBL5995059
6.26	IC50	550	nM	CHEMBL5868709
6.26	IC50	550	nM	CHEMBL5938578
6.26	IC50	550	nM	CHEMBL5830317
6.26	IC50	550	nM	CHEMBL5755230
6.26	IC50	550	nM	CHEMBL5881085
6.26	IC50	550	nM	CHEMBL5853100
6.26	IC50	550	nM	CHEMBL5771727
6.26	IC50	550	nM	CHEMBL5912585
6.26	IC50	550	nM	CHEMBL5840207
6.26	IC50	550	nM	CHEMBL6032182
6.26	IC50	550	nM	CHEMBL6054482
6.26	IC50	550	nM	CHEMBL5791182
6.26	IC50	550	nM	CHEMBL5902627
6.26	IC50	550	nM	CHEMBL5886729
6.26	IC50	550	nM	CHEMBL5807733
6.26	IC50	550	nM	CHEMBL5783373
6.26	IC50	550	nM	CHEMBL5745435
6.26	IC50	550	nM	CHEMBL6065488
6.26	IC50	550	nM	CHEMBL5763968
6.26	IC50	550	nM	CHEMBL5912185

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
entinostat	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Rotenone	decreases expression	2
Cadmium Chloride	increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
pyrimidifen	decreases expression	1
abrine	increases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	decreases expression, increases expression, affects cotreatment	1
Fulvestrant	affects cotreatment, decreases methylation	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Calcitriol	increases expression, affects cotreatment	1
Curcumin	decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diethylstilbestrol	increases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Drugs, Chinese Herbal	increases expression	1
Estradiol	increases expression	1
Methapyrilene	increases methylation	1
Naphthoquinones	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4606001	Binding	Inhibition of cezanne (unknown origin)	Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1ZM	Abcam HeLa OTUD7B KO	Cancer cell line	Female
CVCL_TB78	HAP1 OTUD7B (-) 1	Cancer cell line	Male
CVCL_TB79	HAP1 OTUD7B (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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