Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXNX8VL)

• DOT Name: E3 ubiquitin-protein ligase RNF186 (RNF186)
• Synonyms: EC 2.3.2.27; RING finger protein 186
• Gene Name: RNF186
• Related Disease:
  Inflammatory bowel disease
  Metabolic disorder
  Ulcerative colitis
• UniProt ID: RN186_HUMAN
• EC Number: 2.3.2.27
• Sequence:
  MACTKTLQQSQPISAGATTTTTAVAPAGGHSGSTECDLECLVCREPYSCPRLPKLLACQH
  AFCAICLKLLLCVQDNTWSITCPLCRKVTAVPGGLICSLRDHEAVVGQLAQPCTEVSLCP
  QGLVDPADLAAGHPSLVGEDGQDEVSANHVAARRLAAHLLLLALLIILIGPFIYPGVLRW
  VLTFIIALALLMSTLFCCLPSTRGSCWPSSRTLFCREQKHSHISSIA
• Function: E3 ubiquitin protein ligase that is part of an apoptotic signaling pathway activated by endoplasmic reticulum stress. Stimulates the expression of proteins specific of the unfolded protein response (UPR), ubiquitinates BNIP1 and regulates its localization to the mitochondrion and induces calcium release from the endoplasmic reticulum that ultimately leads to cell apoptosis. Plays a role in the maintenance of intestinal homeostasis and clearance of enteric pathogens. Upon NOD2 stimulation, ubiquitinates the ER stress sensor activating transcription factor 6/ATF6 and promotes the unfolded protein response UPR. Participates in basal level of autophagy maintenance by regulating the ubiquitination of EPHB2 and EPHB3. Upon stimulation by ligand EFNB1, ubiquitinates EPHB2 and further recruits MAP1LC3B for autophagy induction. Controls nutrient sensing by ubiquitinating Sestrin-2/SESN2, which is an intracellular sensor of cytosolic leucine and inhibitor of mTORC1 activity.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[1]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[2]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[1]

2 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 E3 ubiquitin-protein ligase RNF186 (RNF186).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase RNF186 (RNF186).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase RNF186 (RNF186).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase RNF186 (RNF186).	[6]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of E3 ubiquitin-protein ligase RNF186 (RNF186).	[7]

References

• [1] Regulation of intestinal homeostasis by the ulcerative colitis-associated gene RNF186.Mucosal Immunol. 2017 Mar;10(2):446-459. doi: 10.1038/mi.2016.58. Epub 2016 Jul 6.
• [2] RNF186 impairs insulin sensitivity by inducing ER stress in mouse primary hepatocytes.Cell Signal. 2018 Dec;52:155-162. doi: 10.1016/j.cellsig.2018.09.008. Epub 2018 Sep 14.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [7] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.