Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8WWM9O)

• DOT Name: Ubiquitin thioesterase OTUB1 (OTUB1)
• Synonyms: EC 3.4.19.12; Deubiquitinating enzyme OTUB1; OTU domain-containing ubiquitin aldehyde-binding protein 1; Otubain-1; hOTU1; Ubiquitin-specific-processing protease OTUB1
• Gene Name: OTUB1
• Related Disease:
  Alzheimer disease
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Chagas disease
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Multiple sclerosis
  Neoplasm
  Neoplasm of esophagus
  Nervous system inflammation
  Ovarian cancer
  Ovarian neoplasm
  Tauopathy
  Gastric cancer
  Glomerulonephritis
  Lupus nephritis
  Metastatic malignant neoplasm
  Nephritis
  Stomach cancer
  Advanced cancer
  Hepatocellular carcinoma
• UniProt ID: OTUB1_HUMAN
• PDB ID: 2ZFY; 3VON; 4DDG; 4DDI; 4DHZ; 4I6L; 4LDT
• EC Number: 3.4.19.12
• Pfam ID: PF10275
• Sequence:
  MAAEEPQQQKQEPLGSDSEGVNCLAYDEAIMAQQDRIQQEIAVQNPLVSERLELSVLYKE
  YAEDDNIYQQKIKDLHKKYSYIRKTRPDGNCFYRAFGFSHLEALLDDSKELQRFKAVSAK
  SKEDLVSQGFTEFTIEDFHNTFMDLIEQVEKQTSVADLLASFNDQSTSDYLVVYLRLLTS
  GYLQRESKFFEHFIEGGRTVKEFCQQEVEPMCKESDHIHIIALAQALSVSIQVEYMDRGE
  GGTTNPHIFPEGSEPKVYLLYRPGHYDILYK
• 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.
• 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.
• Reactome Pathway:
  Ovarian tumor domain proteases (R-HSA-5689896)
  Ub-specific processing proteases (R-HSA-5689880)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[4]
Chagas disease	DIS8KNVF	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[8]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[4]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[4]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Tauopathy	DISY2IPA	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[11]
Glomerulonephritis	DISPZIQ3	moderate	Altered Expression	[12]
Lupus nephritis	DISCVGPZ	moderate	Altered Expression	[12]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[11]
Nephritis	DISQZQ70	moderate	Altered Expression	[12]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[13]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ubiquitin thioesterase OTUB1 (OTUB1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ubiquitin thioesterase OTUB1 (OTUB1).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Ubiquitin thioesterase OTUB1 (OTUB1).	[17]

3 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ubiquitin thioesterase OTUB1 (OTUB1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Ubiquitin thioesterase OTUB1 (OTUB1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ubiquitin thioesterase OTUB1 (OTUB1).	[18]

References

• [1] Tau interactome mappingbased identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo.Acta Neuropathol. 2017 May;133(5):731-749. doi: 10.1007/s00401-016-1663-9. Epub 2017 Jan 12.
• [2] OTUB1 inhibits CNS autoimmunity by preventing IFN--induced hyperactivation of astrocytes.EMBO J. 2019 May 15;38(10):e100947. doi: 10.15252/embj.2018100947. Epub 2019 Apr 3.
• [3] OTUB1 inhibits the ubiquitination and degradation of FOXM1 in breast cancer and epirubicin resistance.Oncogene. 2016 Mar 17;35(11):1433-44. doi: 10.1038/onc.2015.208. Epub 2015 Jul 6.
• [4] OTUB1 promotes esophageal squamous cell carcinoma metastasis through modulating Snail stability.Oncogene. 2018 Jun;37(25):3356-3368. doi: 10.1038/s41388-018-0224-1. Epub 2018 Mar 21.
• [5] GRAIL and Otubain-1 are Related to T Cell Hyporesponsiveness during Trypanosoma cruzi Infection.PLoS Negl Trop Dis. 2017 Jan 23;11(1):e0005307. doi: 10.1371/journal.pntd.0005307. eCollection 2017 Jan.
• [6] Colon cancer bears overexpression of OTUB1.Pathol Res Pract. 2014 Nov;210(11):770-3. doi: 10.1016/j.prp.2014.05.008. Epub 2014 May 22.
• [7] miR-542-3p inhibits colorectal cancer cell proliferation, migration and invasion by targeting OTUB1.Am J Cancer Res. 2017 Jan 1;7(1):159-172. eCollection 2017.
• [8] OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity.J Biol Chem. 2009 Jun 12;284(24):16135-16145. doi: 10.1074/jbc.M109.007484. Epub 2009 Apr 21.
• [9] The non-coding RNA OTUB1-isoform2 promotes ovarian tumour progression and predicts poor prognosis.J Cell Mol Med. 2018 Oct;22(10):4794-4806. doi: 10.1111/jcmm.13733. Epub 2018 Jul 25.
• [10] The Deubiquitylase OTUB1 Mediates Ferroptosis via Stabilization of SLC7A11.Cancer Res. 2019 Apr 15;79(8):1913-1924. doi: 10.1158/0008-5472.CAN-18-3037. Epub 2019 Feb 1.
• [11] Upregulation of the Non-Coding RNA OTUB1-isoform 2 Contributes to Gastric Cancer Cell Proliferation and Invasion and Predicts Poor Gastric Cancer Prognosis.Int J Biol Sci. 2016 Mar 3;12(5):545-57. doi: 10.7150/ijbs.13540. eCollection 2016.
• [12] OTUB1 overexpression in mesangial cells is a novel regulator in the pathogenesis of glomerulonephritis through the decrease of DCN level.PLoS One. 2012;7(1):e29654. doi: 10.1371/journal.pone.0029654. Epub 2012 Jan 18.
• [13] Expression of OTUB1 in hepatocellular carcinoma and its effects on HCC cell migration and invasion.Acta Biochim Biophys Sin (Shanghai). 2017 Aug 1;49(8):680-688. doi: 10.1093/abbs/gmx056.
• [14] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [15] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [16] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.