OTUB1

Summary

OTUB1 (OTU deubiquitinase, ubiquitin aldehyde binding 1, HGNC:23077) is a protein-coding gene on chromosome 11q13.1, encoding Ubiquitin thioesterase OTUB1 (Q96FW1). Hydrolase that can specifically remove ‘Lys-48’-linked conjugated ubiquitin from proteins and plays an important regulatory role at the level of protein turnover by preventing degradation.

The product of this gene is a member of the OTU (ovarian tumor) superfamily of predicted cysteine proteases. The encoded protein is a highly specific ubiquitin iso-peptidase, and cleaves ubiquitin from branched poly-ubiquitin chains but not from ubiquitinated substrates. It interacts with another ubiquitin protease and an E3 ubiquitin ligase that inhibits cytokine gene transcription in the immune system. It is proposed to function in specific ubiquitin-dependent pathways, possibly by providing an editing function for polyubiquitin chain growth. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55611 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 35 total
• Druggable target: yes
• MANE Select transcript: NM_017670

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23077
Approved symbol	OTUB1
Name	OTU deubiquitinase, ubiquitin aldehyde binding 1
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20113, FLJ40710
Ensembl gene	ENSG00000167770
Ensembl biotype	protein_coding
OMIM	608337
Entrez	55611

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000301453, ENST00000428192, ENST00000447683, ENST00000535140, ENST00000535715, ENST00000536443, ENST00000536943, ENST00000538426, ENST00000541478, ENST00000543004, ENST00000543988, ENST00000890518, ENST00000918068, ENST00000957684

RefSeq mRNA: 1 — MANE Select: NM_017670 NM_017670

CCDS: CCDS8055

Canonical transcript exons

ENST00000538426 — 7 exons

Exon	Start	End
ENSE00001116809	63996857	63996941
ENSE00002216282	63986438	63986514
ENSE00002266669	63997349	63998412
ENSE00003477837	63988337	63988398
ENSE00003586610	63988654	63988752
ENSE00003619574	63996530	63996648
ENSE00003694564	63997050	63997244

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 97.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 107.3731 / max 823.0704, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114849	105.7972	1825
114850	1.5604	788
206325	0.0155	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	97.94	gold quality
prefrontal cortex	UBERON:0000451	97.90	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.40	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.27	gold quality
cerebellar hemisphere	UBERON:0002245	97.14	gold quality
cerebellar cortex	UBERON:0002129	97.10	gold quality
cingulate cortex	UBERON:0003027	97.08	gold quality
anterior cingulate cortex	UBERON:0009835	97.05	gold quality
frontal cortex	UBERON:0001870	97.02	gold quality
neocortex	UBERON:0001950	96.88	gold quality
granulocyte	CL:0000094	96.85	gold quality
pancreatic ductal cell	CL:0002079	96.79	gold quality
ileal mucosa	UBERON:0000331	96.66	gold quality
cervix squamous epithelium	UBERON:0006922	96.64	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.52	gold quality
nucleus accumbens	UBERON:0001882	96.31	gold quality
cerebellum	UBERON:0002037	96.28	gold quality
skin of leg	UBERON:0001511	96.22	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.21	gold quality
amygdala	UBERON:0001876	96.19	gold quality
skin of abdomen	UBERON:0001416	96.18	gold quality
mucosa of transverse colon	UBERON:0004991	96.18	gold quality
right uterine tube	UBERON:0001302	96.14	gold quality
esophagus mucosa	UBERON:0002469	96.10	gold quality
cerebral cortex	UBERON:0000956	96.08	gold quality
stromal cell of endometrium	CL:0002255	95.99	gold quality
cortical plate	UBERON:0005343	95.98	gold quality
tongue squamous epithelium	UBERON:0006919	95.81	gold quality
ganglionic eminence	UBERON:0004023	95.80	gold quality
metanephros cortex	UBERON:0010533	95.77	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

41 targeting OTUB1, 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-6798-5P	100.00	65.77	699
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-2467-3P	98.65	67.18	1969

Literature-anchored findings (GeneRIF, showing 40)

• Structural basis and specificity of human otubain 1-mediated deubiquitination. (PMID:18954305)
• Distinct binding sites for the ubiquitins on either side of the scissile bond allow hOtu1 to discriminate among different isopeptide linkages in polyubiquitin substrates. (PMID:19211026)
• OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells (PMID:19383985)
• Findings suggest that OTUB1 and OTUB2 negatively regulate virus-triggered type I IFN induction and cellular antiviral response by deubiquitinating TRAF3 and -6. (PMID:19996094)
• Post-translational modifications of OTUB1 suggests a new entry point for manipulating Yersinia interactions with the host. (PMID:20553488)
• OTUB1, a deubiquitinating enzyme, is an inhibitor of double-strand break-induced chromatin ubiquitination (PMID:20725033)
• Overexpression of Otub1(D88A) or ablation of endogenous Otub1 by siRNA markedly impaired p53 stabilization and activation in response to DNA damage. Together, these results reveal a novel function for Otub1 in regulating p53 stability and activity (PMID:22124327)
• OTUB1 therefore co-opts Lys48-linked ubiquitin chain recognition to suppress ubiquitin conjugation and the DNA damage response (PMID:22325355)
• structural and biochemical studies elucidating how OTUB1 inhibits UBC13 and other E2 enzymes (PMID:22367539)
• the crystal structure of human OTUB1 in complex with human UBC13 and MMS2 (PMID:22679021)
• These results suggest that OTUB1 regulates NF-kappaB and MAPK signalling pathways and TNF-dependent cell death by modulating c-IAP1 stability. (PMID:23524849)
• A second role of OTUB1-E2 interactions is to stimulate OTUB1 cleavage of Lys48 polyubiquitin. This stimulation is regulated by the ratio of charged to uncharged E2 and by the concentration of Lys48-linked polyubiquitin and free ubiquitin. (PMID:23955022)
• OTUB1 enhances TGF-beta signaling by inhibiting the ubiquitylation and degradation of active SMAD2 and SMAD3. (PMID:24071738)
• These data reveal novel insights into the Otub1 inhibition of E2 wherein monoubiquitination promotes the interaction of Otub1 with UbcH5 and the function to suppress it. (PMID:24403071)
• After viral infection, HSCARG interacted with tumor necrosis receptor-associated factor 3 (TRAF3) and inhibited its ubiquitination by promoting the recruitment of OTUB1 to TRAF3. (PMID:24763515)
• OTUB1 may play an important role in colon cancer development and metastasis. (PMID:24947413)
• OTUB1 promoted the metastasis of CRC cell lines. (PMID:25431208)
• Data show that casein kinase 2 (CK2)-mediated phosphorylation of deubiquitylating enzyme OTUB1 at Ser16 causes nuclear accumulation of OTUB1. (PMID:25872870)
• the data suggest that OTUB1 limits the ubiquitination and degradation of FOXM1 in breast cancer and has a key role in genotoxic agent resistance. (PMID:26148240)
• substrate for hydroxylation by FIH on N22 (PMID:26752685)
• An increase of OTUB1 expression is commonly observed in non-small-cell lung carcinomas harboring wild-type KRAS and is associated with increased levels of ERK1/2 phosphorylation, high Ki67 score, and poorer patient survival. (PMID:26881969)
• Data suggest that inhibiting OTUB1-FOXM1 interaction is a potential avenue for ovarian cancer therapy. (PMID:27167337)
• Data indicate that knockdown of otubain 1 protein (Otub1) reduced the levels of double minute 4 protein (MDMX). (PMID:28035068)
• Silencing of OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) inhibits migration of human glioma cells in vitro. Study results suggested that OTUB1 was a valuable marker in the pathogenesis of human gliomas and could be used as a novel biomarker for glioma therapy in the future. (PMID:28139865)
• Overexpression of OTUB1 (OTU domain-containing ubiquitin aldehyde binding protein 1) in hepatocellular carcinoma (HCC) could be a supplementary biomarker for HCC because it plays a vital role in the progression of HCC. (PMID:28575188)
• findings reveal a mechanism that stabilizes the mTORC1 inhibitor DEPTOR via OTUB1’s deubiquitinase activity. (PMID:29382726)
• High OTUB1 expression is associated with esophageal squamous cell carcinoma metastasis through modulating Snail stability. (PMID:29559747)
• our study suggested that OTUB1-isoform2 is a novel prognostic biomarker with independent oncogenic functions for ovarian cancer. (PMID:30044532)
• OTUB1 depletion dramatically destabilizes the E2-conjugating enzyme UBE2E1 in both mouse and human OTUB1 knockout cell lines. (PMID:30282802)
• addition of FAT10 also led to an increased interaction between OTUB1 and its cognate E2 UbcH5B, implying a function of FAT10 in the inhibition of polyubiquitylation (PMID:30718280)
• These findings suggest that OTUB1 is an important regulator of Nur77 stability and plays a role in controlling the inflammatory response. (PMID:30905540)
• The Otub1 deficiency not only promotes signal-induced p100 processing and noncanonical NF-kappaB activation but also causes steady-state p100 degradation, leading to aberrant NF-kappaB activation in the canonical pathway. (PMID:31086255)
• OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1. (PMID:32023470)
• Activation and selectivity of OTUB-1 and OTUB-2 deubiquitinylases. (PMID:32265297)
• OTUB1 stabilizes mismatch repair protein MSH2 by blocking ubiquitination. (PMID:33640455)
• OTUB1 facilitates bladder cancer progression by stabilizing ATF6 in response to endoplasmic reticulum stress. (PMID:33686769)
• Endogenous hydrogen sulfide regulates xCT stability through persulfidation of OTUB1 at cysteine 91 in colon cancer cells. (PMID:33878705)
• Molecular recognition and deubiquitination of cyclic K48-linked ubiquitin chains by OTUB1. (PMID:34049206)
• OTUB1 knockdown promotes apoptosis in melanoma cells by upregulating TRAIL expression. (PMID:34488924)
• The deubiquitinase OTUB1 fosters papillary thyroid carcinoma growth through EYA1 stabilization. (PMID:34773364)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	otub1b	ENSDARG00000011462
danio_rerio	otub1a	ENSDARG00000055536
mus_musculus	Otub1	ENSMUSG00000024767
rattus_norvegicus	Otub1l1	ENSRNOG00000009072
rattus_norvegicus	Otub1	ENSRNOG00000021175
drosophila_melanogaster	CG4968	FBGN0032214
caenorhabditis_elegans		WBGENE00007718

Paralogs (1): OTUB2 (ENSG00000089723)

Protein

Protein identifiers

Ubiquitin thioesterase OTUB1 — Q96FW1 (reviewed: Q96FW1)

Alternative names: Deubiquitinating enzyme OTUB1, OTU domain-containing ubiquitin aldehyde-binding protein 1, Otubain-1, Ubiquitin-specific-processing protease OTUB1

All UniProt accessions (6): Q96FW1, F5GYJ8, F5GYN4, F5H3F0, F5H4F3, F5H6Q1

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolase that can specifically remove ‘Lys-48’-linked conjugated ubiquitin from proteins and plays an important regulatory role at the level of protein turnover by preventing degradation. Regulator of T-cell anergy, a phenomenon that occurs when T-cells are rendered unresponsive to antigen rechallenge and no longer respond to their cognate antigen. Acts via its interaction with RNF128/GRAIL, a crucial inductor of CD4 T-cell anergy. Isoform 1 destabilizes RNF128, leading to prevent anergy. In contrast, isoform 2 stabilizes RNF128 and promotes anergy. Surprisingly, it regulates RNF128-mediated ubiquitination, but does not deubiquitinate polyubiquitinated RNF128. Deubiquitinates estrogen receptor alpha (ESR1). Mediates deubiquitination of ‘Lys-48’-linked polyubiquitin chains, but not ‘Lys-63’-linked polyubiquitin chains. Not able to cleave di-ubiquitin. Also capable of removing NEDD8 from NEDD8 conjugates, but with a much lower preference compared to ‘Lys-48’-linked ubiquitin. Plays a key non-catalytic role in DNA repair regulation by inhibiting activity of RNF168, an E3 ubiquitin-protein ligase that promotes accumulation of ‘Lys-63’-linked histone H2A and H2AX at DNA damage sites. Inhibits RNF168 independently of ubiquitin thioesterase activity by binding and inhibiting UBE2N/UBC13, the E2 partner of RNF168, thereby limiting spreading of ‘Lys-63’-linked histone H2A and H2AX marks. Inhibition occurs by binding to free ubiquitin: free ubiquitin acts as an allosteric regulator that increases affinity for UBE2N/UBC13 and disrupts interaction with UBE2V1. The OTUB1-UBE2N/UBC13-free ubiquitin complex adopts a configuration that mimics a cleaved ‘Lys48’-linked di-ubiquitin chain. Acts as a regulator of mTORC1 and mTORC2 complexes. When phosphorylated at Tyr-26, acts as an activator of the mTORC1 complex by mediating deubiquitination of RPTOR via a non-catalytic process: acts by binding and inhibiting the activity of the ubiquitin-conjugating enzyme E2 (UBE2D1/UBCH5A, UBE2W/UBC16 and UBE2N/UBC13), thereby preventing ubiquitination of RPTOR. Can also act as an inhibitor of the mTORC1 and mTORC2 complexes in response to amino acids by mediating non-catalytic deubiquitination of DEPTOR.

Subunit / interactions. Interacts with FUS and RACK1. Interacts with UBE2D1/UBCH5A, UBE2W/UBC16 and UBE2N/UBC13. Interacts with RNF128. Forms a ternary complex with RNF128 and USP8. Interacts with the C-terminal UCH catalytic domain of USP8. Interacts with RNF128. Does not associate with USP8.

Subcellular location. Cytoplasm.

Tissue specificity. Isoform 1 is ubiquitous. Isoform 2 is expressed only in lymphoid tissues such as tonsils, lymph nodes and spleen, as well as peripheral blood mononuclear cells.

Post-translational modifications. Phosphorylation at Tyr-26 by SRC and SRMS promotes deubiquitination of RPTOR via a non-catalytic process.

Activity regulation. By free ubiquitin: binding of free ubiquitin triggers conformational changes in the OTU domain and formation of a ubiquitin-binding helix in the N-terminus, promoting binding of the conjugated donor ubiquitin in UBE2N/UBC13 to OTUB1.

Domain organisation. In addition to ubiquitin-binding at the Cys-91 active site, a proximal ubiquitin-binding site is also present at Cys-23 Occupancy of the active site is needed to enable tight binding to the second site. Distinct binding sites for the ubiquitins may allow to discriminate among different isopeptide linkages (i.e. ‘Lys-48’-, ‘Lys-63’-linked polyubiquitin) in polyubiquitin substrates and achieve linkage-specific deubiquitination.

Miscellaneous. In the structure described by PubMed:18954305, the His-265 active site of the catalytic triad is located too far to interact directly with the active site Cys-91. A possible explanation is that OTUB1 is in inactive conformation in absence of ubiquitin and a conformation change may move His-265 in the proximity of Cys-91 in presence of ubiquitin substrate. Lacks the catalytic sites for protease activity.

Similarity. Belongs to the peptidase C65 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96FW1-1	1, Otubain-1	yes
Q96FW1-2	2, ARF-1

RefSeq proteins (1): NP_060140* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003323	OTU_dom	Domain
IPR016615	Otubain	Family
IPR019400	Peptidase_C65_otubain	Family
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR042467	Peptidase_C65_otubain_sub2	Homologous_superfamily
IPR042468	Peptidase_C65_otubain_sub1	Homologous_superfamily

Pfam: PF10275

UniProt features (67 total): mutagenesis site 21, helix 12, strand 9, site 6, region of interest 6, active site 3, modified residue 3, sequence conflict 2, initiator methionine 1, chain 1, domain 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
2ZFY	X-RAY DIFFRACTION	1.69
4LDT	X-RAY DIFFRACTION	1.9
4I6L	X-RAY DIFFRACTION	2.49
4DHZ	X-RAY DIFFRACTION	3.11
3VON	X-RAY DIFFRACTION	3.15
4DDG	X-RAY DIFFRACTION	3.3
4DDI	X-RAY DIFFRACTION	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96FW1-F1	92.19	0.89

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (9): 91 (nucleophile); 265; 23 (required for proximal ubiquitin-binding); 221 (interacts with free ubiquitin); 235 (interacts with free ubiquitin); 237 (interacts with free ubiquitin); 261 (interacts with free ubiquitin); 266 (interacts with free ubiquitin); 88

Post-translational modifications (3): 2, 16, 26

Mutagenesis-validated functional residues (21):

Position	Phenotype
23	abolishes only ubiquitin-vinylsulfone adduct formation.
23	does not affect ability to deubiquitinate deptor.
26	abolished ability to deubiquitinate rptor.
33	impairs inhibition of ube2n/ubc13.
37	impairs inhibition of ube2n/ubc13.
39	does not affect activity in dna repair and ability to inhibit ube2n/ubc13.
87	slightly improves ability to cleave ‘k63’-linked ubiquitin.
88	abolished ability to deubiquitinate deptor. does not affect ability to deubiquitinate rptor; when associated with a-91 a
88	abolishes hydrolase activity in vitro. abolishes ability to inhibit rnf168; when associated with s-91 and a-265.
91	prevents rnf128 autoubiquitination, and stabilizes rnf128 in vivo. abolishes both ubiquitin-binding and adduct formation
91	abolishes hydrolase activity in vitro. does not affect ability to inhibit rnf168. does not affect ability to deubiquitin
116	does not affect ability to inhibit ube2n/ubc13.
134	impairs inhibition of ube2n/ubc13.
137	impairs inhibition of ube2n/ubc13.
176	no effect on rnf128.
190	fails to inhibit ubiquitin conjugation by ube2n/ubc13.
212	no effect on rnf128.
261	impairs inhibition of ube2n/ubc13.
263	fails to inhibit ubiquitin conjugation by ube2n/ubc13.
265	abolishes ability to inhibit rnf168; when associated with a-88 and s-91. does not affect ability to deubiquitinate rptor
265	abolishes hydrolase activity in vitro.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases
R-HSA-5689896	Ovarian tumor domain proteases

MSigDB gene sets: 160 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, YAGI_AML_WITH_INV_16_TRANSLOCATION, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_NEGATIVE_REGULATION_OF_DNA_REPAIR, MORF_UBE2I, MAZ_Q6, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, chr11q13, GOBP_REGULATION_OF_DNA_REPAIR, MORF_RAF1, ONKEN_UVEAL_MELANOMA_UP, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_DNA_DAMAGE_RESPONSE

GO Biological Process (13): adaptive immune response (GO:0002250), DNA repair (GO:0006281), proteolysis (GO:0006508), DNA damage response (GO:0006974), protein deubiquitination (GO:0016579), protein K48-linked deubiquitination (GO:0071108), positive regulation of TORC1 signaling (GO:1904263), negative regulation of double-strand break repair (GO:2000780), immune system process (GO:0002376), cellular response to nutrient levels (GO:0031669), TORC1 signaling (GO:0038202), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of TORC1 signaling (GO:1904262)

GO Molecular Function (9): cysteine-type deubiquitinase activity (GO:0004843), deNEDDylase activity (GO:0019784), ubiquitin protein ligase binding (GO:0031625), ubiquitin binding (GO:0043130), ubiquitin-protein transferase inhibitor activity (GO:0055105), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deubiquitination	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
TORC1 signaling	2
regulation of TORC1 signaling	2
immune response	1
DNA metabolic process	1
DNA damage response	1
protein metabolic process	1
cellular response to stress	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
protein deubiquitination	1
positive regulation of TOR signaling	1
double-strand break repair	1
negative regulation of DNA repair	1
regulation of double-strand break repair	1
biological_process	1
response to nutrient levels	1
cellular response to stimulus	1
TOR signaling	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
negative regulation of TOR signaling	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
ubiquitin-like protein peptidase activity	1
ubiquitin-like protein ligase binding	1
ubiquitin-like protein binding	1
ubiquitin-protein transferase activity	1
enzyme inhibitor activity	1
ubiquitin-protein transferase regulator activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
nuclear lumen	1
cytoplasm	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2028 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTUB1	UBE2N	P61088	998
OTUB1	USP8	P40818	921
OTUB1	ZUP1	Q96AP4	891
OTUB1	RNF168	Q8IYW5	875
OTUB1	UBE2S	Q16763	823
OTUB1	UBE2D1	P51668	821
OTUB1	RNF128	Q8TEB7	769
OTUB1	RNF8	O76064	754
OTUB1	OTUD3	Q5T2D3	746
OTUB1	TRAF6	Q9Y4K3	745
OTUB1	UBE2D2	P51669	743
OTUB1	OTUD5	Q96G74	733
OTUB1	OTUD7B	Q6GQQ9	713
OTUB1	USP2	O75604	704
OTUB1	OTULIN	Q96BN8	682
OTUB1	YOD1	Q5VVQ6	682

IntAct

310 interactions, top by confidence:

A	B	Type	Score
OTUB1	UBE2D2	psi-mi:“MI:0915”(physical association)	0.920
UBE2D2	OTUB1	psi-mi:“MI:0915”(physical association)	0.920
UBE2D3	OTUB1	psi-mi:“MI:0915”(physical association)	0.870
OTUB1	UBE2D3	psi-mi:“MI:0915”(physical association)	0.870
UBE2D1	OTUB1	psi-mi:“MI:0915”(physical association)	0.850
OTUB1	UBE2D4	psi-mi:“MI:0915”(physical association)	0.830
UBE2D4	OTUB1	psi-mi:“MI:0915”(physical association)	0.830
UBE2E3	OTUB1	psi-mi:“MI:0915”(physical association)	0.800
OTUB1	UBE2E2	psi-mi:“MI:0915”(physical association)	0.800
HIF1AN	OTUB1	psi-mi:“MI:0210”(hydroxylation reaction)	0.760
UBE2E2	RNF25	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
OTUB1	TTR	psi-mi:“MI:0915”(physical association)	0.670
OTUB1	UBA1	psi-mi:“MI:0915”(physical association)	0.670
PARK7	OTUB1	psi-mi:“MI:0915”(physical association)	0.670
TARDBP	OTUB1	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (584): OTUB1 (Affinity Capture-MS), OTUB1 (Two-hybrid), OTUB1 (Two-hybrid), UBC (Reconstituted Complex), UBE2D2 (Reconstituted Complex), OTUB1 (Biochemical Activity), OTUB1 (Reconstituted Complex), OTUB1 (Affinity Capture-MS), UBC (Biochemical Activity), UBC (Co-crystal Structure), NEDD8 (Biochemical Activity), OTUB1 (Affinity Capture-MS), OTUB1 (Affinity Capture-MS), OTUB1 (Affinity Capture-MS), OTUB1 (Biochemical Activity)

ESM2 similar proteins: A1Z6M6, A3KQS4, A8XDJ2, B2RYG6, G5EES6, H9IWW7, O00170, O02334, O08915, O13648, O13974, O17850, O42646, O97628, P33313, P38747, P40483, P43558, P48608, P53155, P91133, Q08930, Q09874, Q29FC9, Q3SWY8, Q54M20, Q55BI3, Q5FWY5, Q60XN1, Q6C4F8, Q6CQ60, Q6T486, Q75IP6, Q7TQI3, Q7YRC1, Q96FW1, Q9FQ09, Q9I7X6, Q9M117, Q9N4H4

Diamond homologs: A8XDJ2, B2RYG6, Q7TQI3, Q8LG98, Q96DC9, Q96FW1, Q9CQX0, Q9VL00, Q9XVR6

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
OTUB1	down-regulates	UBE2N	binding
CSNK2A1	“up-regulates activity”	OTUB1	phosphorylation
OTUB1	“up-regulates quantity by stabilization”	TP53	deubiquitination
OTUB1	“down-regulates activity”	ESR1	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
TICAM1, RIP1-mediated IKK complex recruitment	5	43.5×	8e-06
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	7	37.4×	1e-07
IKK complex recruitment mediated by RIP1	5	36.0×	2e-05
PINK1-PRKN Mediated Mitophagy	6	31.0×	5e-06
Negative regulators of DDX58/IFIH1 signaling	6	28.4×	7e-06
Aggrephagy	5	18.0×	5e-04
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	6	17.1×	9e-05
E3 ubiquitin ligases ubiquitinate target proteins	6	16.8×	9e-05

GO biological processes:

GO term	Partners	Fold	FDR
amyloid fibril formation	6	45.7×	3e-06
adult locomotory behavior	7	26.7×	3e-06
protein monoubiquitination	6	26.1×	2e-05
protein K11-linked ubiquitination	5	24.8×	2e-04
protein K48-linked ubiquitination	8	17.1×	6e-06
protein K63-linked ubiquitination	5	16.9×	1e-03
negative regulation of neuron apoptotic process	9	12.6×	8e-06
ubiquitin-dependent protein catabolic process	11	10.3×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2258 predictions. Top by Δscore:

Variant	Effect	Δscore
11:63986512:AAGG:A	donor_loss	1.0000
11:63986513:AGGT:A	donor_loss	1.0000
11:63986514:GGTA:G	donor_loss	1.0000
11:63986515:G:GA	donor_loss	1.0000
11:63986516:T:G	donor_loss	1.0000
11:63988334:CAG:C	acceptor_loss	1.0000
11:63988335:A:AG	acceptor_gain	1.0000
11:63988335:A:AT	acceptor_loss	1.0000
11:63988335:AG:A	acceptor_gain	1.0000
11:63988335:AGGT:A	acceptor_gain	1.0000
11:63988336:G:GA	acceptor_gain	1.0000
11:63988336:GG:G	acceptor_gain	1.0000
11:63988336:GGT:G	acceptor_gain	1.0000
11:63988336:GGTG:G	acceptor_gain	1.0000
11:63988336:GGTGT:G	acceptor_gain	1.0000
11:63988395:AGAGG:A	donor_loss	1.0000
11:63988396:G:GT	donor_gain	1.0000
11:63988396:GAG:G	donor_gain	1.0000
11:63988396:GAGGT:G	donor_loss	1.0000
11:63988397:AGGT:A	donor_loss	1.0000
11:63988399:GT:G	donor_loss	1.0000
11:63988400:T:G	donor_loss	1.0000
11:63988653:GATT:G	acceptor_gain	1.0000
11:63988751:AG:A	donor_loss	1.0000
11:63996637:G:GT	donor_gain	1.0000
11:63996638:G:GT	donor_gain	1.0000
11:63996646:GCG:G	donor_gain	1.0000
11:63996649:G:GG	donor_gain	1.0000
11:63996942:G:GG	donor_gain	1.0000
11:63996942:GTGAG:G	donor_loss	1.0000

AlphaMissense

1795 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:63988363:G:C	A29P	1.000
11:63988372:G:C	A32P	1.000
11:63988388:T:A	I37N	1.000
11:63988388:T:C	I37T	1.000
11:63988388:T:G	I37S	1.000
11:63988657:G:C	A42P	1.000
11:63988735:T:G	Y68D	1.000
11:63996534:T:C	L75P	1.000
11:63996557:C:A	R83S	1.000
11:63996557:C:G	R83G	1.000
11:63996558:G:C	R83P	1.000
11:63996566:A:T	R86W	1.000
11:63996567:G:C	R86T	1.000
11:63996567:G:T	R86M	1.000
11:63996568:G:C	R86S	1.000
11:63996568:G:T	R86S	1.000
11:63996572:G:C	D88H	1.000
11:63996572:G:T	D88Y	1.000
11:63996573:A:T	D88V	1.000
11:63996574:C:A	D88E	1.000
11:63996574:C:G	D88E	1.000
11:63996575:G:A	G89S	1.000
11:63996575:G:C	G89R	1.000
11:63996575:G:T	G89C	1.000
11:63996576:G:A	G89D	1.000
11:63996576:G:C	G89A	1.000
11:63996576:G:T	G89V	1.000
11:63996579:A:T	N90I	1.000
11:63996580:C:A	N90K	1.000
11:63996580:C:G	N90K	1.000

dbSNP variants (sampled 300 via entrez): RS1000236916 (11:63995415 C>T), RS1000493376 (11:63990584 T>A), RS1000928723 (11:63991006 G>C,T), RS1000973316 (11:63996100 A>G), RS1001441355 (11:63989106 G>A), RS1001872469 (11:63989864 A>C,T), RS1001987135 (11:63990163 C>T), RS1002782841 (11:63994869 TGAG>T), RS1002879037 (11:63988531 T>C), RS1002984263 (11:63984664 T>A), RS1003111795 (11:63990883 T>C), RS1003123378 (11:63992413 G>A,C), RS1003759348 (11:63998612 A>C), RS1003947619 (11:63994370 A>C,G), RS1004339138 (11:63991183 C>A)

Disease associations

OMIM: gene MIM:608337 | 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
GCST008103_34	Bipolar disorder	6.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523428 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C65: Otubains

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

Ligand	Action	Affinity	Parameter
compound 61 [PMID: 36221183]	Inhibition	9.77	pIC50

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
9.77	IC50	0.17	nM	CHEMBL5185273
9.38	IC50	0.42	nM	CHEMBL5173239
8.77	IC50	1.7	nM	CHEMBL5172138
8.15	IC50	7.1	nM	CHEMBL5196686
7.43	IC50	37	nM	CHEMBL5180901
6.18	Kd	654.7	nM	CHEMBL5653589
6.18	ED50	654.7	nM	CHEMBL5653589
5.42	Kd	3765	nM	CHEMBL3752910
5.42	ED50	3765	nM	CHEMBL3752910
5.21	IC50	6119	nM	CHEMBL5190411

PubChem BioAssay actives

8 with measured affinity, of 161 total; 8 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
2-[2-chloro-6-fluoro-3-[(3R)-1-methylpyrrolidin-3-yl]oxyphenyl]benzo[f][1,3]benzoxazole-4,9-dione	1857647: Inhibition of N-terminal His-6 tagged OTUB1 (40 to 271 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using Ub-Rho measured after 0.5 to 3 hrs by fluorescence based Plate reader method	ic50	0.0002	uM
2-[6-chloro-2-fluoro-3-[(3R)-1-methylpyrrolidin-3-yl]oxyphenyl]benzo[f][1,3]benzoxazole-4,9-dione	1857647: Inhibition of N-terminal His-6 tagged OTUB1 (40 to 271 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using Ub-Rho measured after 0.5 to 3 hrs by fluorescence based Plate reader method	ic50	0.0004	uM
2-pyridin-3-ylbenzo[f][1,3]benzoxazole-4,9-dione	1857647: Inhibition of N-terminal His-6 tagged OTUB1 (40 to 271 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using Ub-Rho measured after 0.5 to 3 hrs by fluorescence based Plate reader method	ic50	0.0017	uM
2-[2-chloro-5-[(3R)-1-methylpyrrolidin-3-yl]oxyphenyl]benzo[f][1,3]benzoxazole-4,9-dione	1857647: Inhibition of N-terminal His-6 tagged OTUB1 (40 to 271 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using Ub-Rho measured after 0.5 to 3 hrs by fluorescence based Plate reader method	ic50	0.0071	uM
2-[3-[(3R)-1-[2-(3-but-3-ynyldiazirin-3-yl)ethyl]pyrrolidin-3-yl]oxyphenyl]benzo[f][1,3]benzoxazole-4,9-dione	1857647: Inhibition of N-terminal His-6 tagged OTUB1 (40 to 271 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using Ub-Rho measured after 0.5 to 3 hrs by fluorescence based Plate reader method	ic50	0.0370	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148921: Binding affinity to human OTUB1 incubated for 45 mins by Kinobead based pull down assay	kd	0.6547	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148921: Binding affinity to human OTUB1 incubated for 45 mins by Kinobead based pull down assay	kd	3.7650	uM
2-[3-[(3R)-1-[2-(3-but-3-ynyldiazirin-3-yl)ethyl]pyrrolidin-3-yl]oxyphenyl]-1H-benzo[f]benzimidazole-4,9-dione	1857647: Inhibition of N-terminal His-6 tagged OTUB1 (40 to 271 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using Ub-Rho measured after 0.5 to 3 hrs by fluorescence based Plate reader method	ic50	6.1190	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases methylation	5
Smoke	increases expression, decreases expression, increases abundance	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	increases mutagenesis, affects methylation	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
4-hydroxy-2-nonenal	increases stability, affects binding, decreases abundance, decreases ubiquitination	1
coumarin	increases phosphorylation	1
2-palmitoylglycerol	increases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Curcumin	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Diuron	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ferrous Compounds	affects binding, decreases abundance, decreases ubiquitination, increases stability	1
Furaldehyde	affects cotreatment, affects localization, decreases expression	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4358853	Binding	Inhibition of recombinant human His6-Otubain-1 assessed as reduction in cleavage of luminescent substrate Ub-AML at 100 uM	Re-Evaluating the Mechanism of Action of α,β-Unsaturated Carbonyl DUB Inhibitors b-AP15 and VLX1570: A Paradigmatic Example of Unspecific Protein Cross-linking with Michael Acceptor Motif-Containing Drugs. — J Med Chem

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_B3D5	Abcam HEK293T OTUB1 KO	Transformed cell line	Female
CVCL_TB67	HAP1 OTUB1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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