Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU1NS9O)

• DOT Name: E3 ubiquitin-protein ligase RNF185 (RNF185)
• Synonyms: EC 2.3.2.27; RING finger protein 185
• Gene Name: RNF185
• Related Disease:
  Diabetic kidney disease
  Systemic lupus erythematosus
  Gastric cancer
  Stomach cancer
• UniProt ID: RN185_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF00097
• Sequence:
  MASKGPSASASPENSSAGGPSGSSNGAGESGGQDSTFECNICLDTAKDAVISLCGHLFCW
  PCLHQWLETRPNRQVCPVCKAGISRDKVIPLYGRGSTGQQDPREKTPPRPQGQRPEPENR
  GGFQGFGFGDGGFQMSFGIGAFPFGIFATAFNINDGRPPPAVPGTPQYVDEQFLSRLFLF
  VALVIMFWLLIA
• Function: E3 ubiquitin-protein ligase that regulates selective mitochondrial autophagy by mediating 'Lys-63'-linked polyubiquitination of BNIP1. Acts in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, which targets misfolded proteins that accumulate in the endoplasmic reticulum (ER) for ubiquitination and subsequent proteasome-mediated degradation. Protects cells from ER stress-induced apoptosis. Responsible for the cotranslational ubiquitination and degradation of CFTR in the ERAD pathway. Also acts as a regulator of the innate antiviral response by catalyzing 'Lys-27'-linked polyubiquitination of CGAS at 'Lys-173' and 'Lys-384', thereby promoting CGAS cyclic GMP-AMP synthase activity. Preferentially associates with the E2 enzymes UBE2J1 and UBE2J2.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Defective CFTR causes cystic fibrosis (R-HSA-5678895)
  ER Quality Control Compartment (ERQC) (R-HSA-901032)
  ABC-family proteins mediated transport (R-HSA-382556)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic kidney disease	DISJMWEY	Definitive	Genetic Variation	[1]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[3]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of E3 ubiquitin-protein ligase RNF185 (RNF185).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF185 (RNF185).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase RNF185 (RNF185).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of E3 ubiquitin-protein ligase RNF185 (RNF185).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of E3 ubiquitin-protein ligase RNF185 (RNF185).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase RNF185 (RNF185).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase RNF185 (RNF185).	[10]

References

• [1] A genome-wide association study for diabetic nephropathy genes in African Americans.Kidney Int. 2011 Mar;79(5):563-72. doi: 10.1038/ki.2010.467. Epub 2010 Dec 8.
• [2] The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune response.PLoS Pathog. 2017 Mar 8;13(3):e1006264. doi: 10.1371/journal.ppat.1006264. eCollection 2017 Mar.
• [3] RNF185 modulates JWA ubiquitination and promotes gastric cancer metastasis.Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1552-1561. doi: 10.1016/j.bbadis.2018.02.013. Epub 2018 Feb 23.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.