Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7VW6RP)

• DOT Name: E3 ubiquitin-protein ligase TRIM31 (TRIM31)
• Synonyms: EC 2.3.2.27; Tripartite motif-containing protein 31
• Gene Name: TRIM31
• Related Disease:
  Hepatitis B virus infection
  Ankylosing spondylitis
  Attention deficit hyperactivity disorder
  Autoimmune thyroid disease
  Barrett esophagus
  Breast carcinoma
  Esophageal adenocarcinoma
  Familial multiple trichoepithelioma
  Gastric cancer
  Glioma
  Hemochromatosis
  Hepatocellular carcinoma
  Irritant contact dermatitis
  Lung adenocarcinoma
  Major depressive disorder
  Mental disorder
  Myasthenia gravis
  Prostate carcinoma
  Rheumatoid arthritis
  Schizophrenia
  Stomach cancer
  Type-1 diabetes
  Type-1/2 diabetes
  Vitiligo
  Advanced cancer
  Colorectal carcinoma
  Pancreatic cancer
  Gallbladder cancer
  Gallbladder carcinoma
  Lung cancer
  Metastatic malignant neoplasm
  Systemic lupus erythematosus
  Tuberous sclerosis
• UniProt ID: TRI31_HUMAN
• PDB ID: 2YSJ; 2YSL
• EC Number: 2.3.2.27
• Pfam ID: PF00643 ; PF15227
• Sequence:
  MASGQFVNKLQEEVICPICLDILQKPVTIDCGHNFCLKCITQIGETSCGFFKCPLCKTSV
  RKNAIRFNSLLRNLVEKIQALQASEVQSKRKEATCPRHQEMFHYFCEDDGKFLCFVCRES
  KDHKSHNVSLIEEAAQNYQGQIQEQIQVLQQKEKETVQVKAQGVHRVDVFTDQVEHEKQR
  ILTEFELLHQVLEEEKNFLLSRIYWLGHEGTEAGKHYVASTEPQLNDLKKLVDSLKTKQN
  MPPRQLLEDIKVVLCRSEEFQFLNPTPVPLELEKKLSEAKSRHDSITGSLKKFKDQLQAD
  RKKDENRFFKSMNKNDMKSWGLLQKNNHKMNKTSEPGSSSAGGRTTSGPPNHHSSAPSHS
  LFRASSAGKVTFPVCLLASYDEISGQGASSQDTKTFDVALSEELHAALSEWLTAIRAWFC
  EVPSS
• Function: E3 ubiquitin-protein ligase that acts as a regulator of antiviral immune response and inflammation by mediating ubiquitination of substrates. Acts as a regulator of innate immune defense against viruses by mediating 'Lys-63'-linked ubiquitination of MAVS, promoting MAVS polymerization and formation of three-stranded helical filaments on mitochondria. Acts as a negative regulator of the NLRP3 inflammasome by catalyzing 'Lys-48'-linked ubiquitination of NLRP3, leading to its degradation. Regulator of Src-induced anchorage independent cell growth.
• Tissue Specificity: Up-regulated in gastric adenocarcinomas.
• Reactome Pathway: Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis B virus infection	DISLQ2XY	Definitive	Biomarker	[1]
Ankylosing spondylitis	DISRC6IR	Strong	Genetic Variation	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[3]
Autoimmune thyroid disease	DISIHC6A	Strong	Genetic Variation	[4]
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Esophageal adenocarcinoma	DISODWFP	Strong	Altered Expression	[5]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[7]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Hemochromatosis	DISAPY0H	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
Irritant contact dermatitis	DIS62JY3	Strong	Biomarker	[11]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[12]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[13]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[3]
Myasthenia gravis	DISELRCI	Strong	Genetic Variation	[14]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[15]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[16]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[17]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[7]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[4]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[18]
Vitiligo	DISR05SL	Strong	Genetic Variation	[19]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[20]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[20]
Pancreatic cancer	DISJC981	moderate	Biomarker	[21]
Gallbladder cancer	DISXJUAF	Limited	Biomarker	[22]
Gallbladder carcinoma	DISD6ACL	Limited	Biomarker	[22]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[23]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[24]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[25]
Tuberous sclerosis	DISEMUGZ	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase TRIM31 (TRIM31).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase TRIM31 (TRIM31).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase TRIM31 (TRIM31).	[28]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of E3 ubiquitin-protein ligase TRIM31 (TRIM31).	[30]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of E3 ubiquitin-protein ligase TRIM31 (TRIM31).	[31]
Capecitabine	DMTS85L	Approved	Capecitabine increases the expression of E3 ubiquitin-protein ligase TRIM31 (TRIM31).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase TRIM31 (TRIM31).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of E3 ubiquitin-protein ligase TRIM31 (TRIM31).	[33]

References

• [1] Type-I-IFN-Stimulated Gene TRIM5 Inhibits HBV Replication by Promoting HBx Degradation.Cell Rep. 2019 Dec 10;29(11):3551-3563.e3. doi: 10.1016/j.celrep.2019.11.041.
• [2] Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility.Nat Genet. 2011 Jul 10;43(8):761-7. doi: 10.1038/ng.873.
• [3] The ATXN1 and TRIM31 genes are related to intelligence in an ADHD background: evidence from a large collaborative study totaling 4,963 subjects.Am J Med Genet B Neuropsychiatr Genet. 2011 Mar;156(2):145-57. doi: 10.1002/ajmg.b.31149. Epub 2010 Dec 16.
• [4] Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes.J Autoimmun. 2015 Jun;60:32-9. doi: 10.1016/j.jaut.2015.03.006. Epub 2015 Apr 27.
• [5] RING finger proteins are involved in the progression of barrett esophagus to esophageal adenocarcinoma: a preliminary study.Gut Liver. 2014 Sep;8(5):487-94. doi: 10.5009/gnl13133. Epub 2014 Feb 24.
• [6] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [7] The cellular level of TRIM31, an RBCC protein overexpressed in gastric cancer, is regulated by multiple mechanisms including the ubiquitin-proteasome system.Cell Biol Int. 2011 Jul;35(7):657-61. doi: 10.1042/CBI20100772.
• [8] TRIM31 promotes glioma proliferation and invasion through activating NF-B pathway.Onco Targets Ther. 2019 Mar 27;12:2289-2297. doi: 10.2147/OTT.S183625. eCollection 2019.
• [9] Localization of seven new genes around the HLA-A locus.Hum Mol Genet. 1993 Jan;2(1):55-60. doi: 10.1093/hmg/2.1.55.
• [10] TRIM31 is upregulated in hepatocellular carcinoma and promotes disease progression by inducing ubiquitination of TSC1-TSC2 complex.Oncogene. 2018 Jan 25;37(4):478-488. doi: 10.1038/onc.2017.349. Epub 2017 Oct 2.
• [11] Association of MHC region SNPs with irritant susceptibility in healthcare workers. J Immunotoxicol. 2016 Sep;13(5):738-44. doi: 10.3109/1547691X.2016.1173135. Epub 2016 Jun 3.
• [12] A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma.Am J Hum Genet. 2009 Nov;85(5):679-91. doi: 10.1016/j.ajhg.2009.09.012. Epub 2009 Oct 15.
• [13] Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways.Nat Commun. 2018 Apr 16;9(1):1470. doi: 10.1038/s41467-018-03819-3.
• [14] Risk for myasthenia gravis maps to a (151) ProAla change in TNIP1 and to human leukocyte antigen-B*08.Ann Neurol. 2012 Dec;72(6):927-35. doi: 10.1002/ana.23691. Epub 2012 Oct 10.
• [15] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [16] REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.Nat Genet. 2009 Jul;41(7):820-3. doi: 10.1038/ng.395. Epub 2009 Jun 7.
• [17] Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.Mol Autism. 2017 May 22;8:21. doi: 10.1186/s13229-017-0137-9. eCollection 2017.
• [18] Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.Nat Commun. 2019 Aug 26;10(1):3842. doi: 10.1038/s41467-019-11704-w.
• [19] Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC.Nat Genet. 2010 Jul;42(7):614-8. doi: 10.1038/ng.603. Epub 2010 Jun 6.
• [20] TRIM31 regulates chronic inflammation via NF-B signal pathway to promote invasion and metastasis in colorectal cancer.Am J Transl Res. 2018 Apr 15;10(4):1247-1259. eCollection 2018.
• [21] Oncogenic TRIM31 confers gemcitabine resistance in pancreatic cancer via activating the NF-B signaling pathway.Theranostics. 2018 May 11;8(12):3224-3236. doi: 10.7150/thno.23259. eCollection 2018.
• [22] Knockdown of TRIM31 suppresses proliferation and invasion of gallbladder cancer cells by down-regulating MMP2/9 through the PI3K/Akt signaling pathway.Biomed Pharmacother. 2018 Jul;103:1272-1278. doi: 10.1016/j.biopha.2018.04.120. Epub 2018 May 7.
• [23] Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.Hum Mol Genet. 2012 Nov 15;21(22):4980-95. doi: 10.1093/hmg/dds334. Epub 2012 Aug 16.
• [24] Tripartite motif 31 promotes resistance to anoikis of hepatocarcinoma cells through regulation of p53-AMPK axis.Exp Cell Res. 2018 Jul 1;368(1):59-66. doi: 10.1016/j.yexcr.2018.04.013. Epub 2018 Apr 14.
• [25] GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.Genes Immun. 2014 Sep;15(6):347-54. doi: 10.1038/gene.2014.23. Epub 2014 May 29.
• [26] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [27] Agonist and antagonist of retinoic acid receptors cause similar changes in gene expression and induce senescence-like growth arrest in MCF-7 breast carcinoma cells. Cancer Res. 2006 Sep 1;66(17):8749-61.
• [28] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [29] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [30] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [31] Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther. 2008 Oct;7(10):1607-18.
• [32] Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids. Toxicol Lett. 2022 Dec 1;371:17-24. doi: 10.1016/j.toxlet.2022.09.013. Epub 2022 Sep 29.
• [33] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.