Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT35B6L5)

• DOT Name: E3 ubiquitin-protein ligase RNF115 (RNF115)
• Synonyms: EC 2.3.2.27; RING finger protein 115; RING-type E3 ubiquitin transferase RNF115; Rab7-interacting RING finger protein; Rabring 7; Zinc finger protein 364
• Gene Name: RNF115
• Related Disease:
  Breast cancer
  Breast neoplasm
  Chromosomal disorder
  Gout
  Breast carcinoma
• UniProt ID: RN115_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13639
• Sequence:
  MAEASAAGADSGAAVAAHRFFCHFCKGEVSPKLPEYICPRCESGFIEEVTDDSSFLGGGG
  SRIDNTTTTHFAELWGHLDHTMFFQDFRPFLSSSPLDQDNRANERGHQTHTDFWGARPPR
  LPLGRRYRSRGSSRPDRSPAIEGILQHIFAGFFANSAIPGSPHPFSWSGMLHSNPGDYAW
  GQTGLDAIVTQLLGQLENTGPPPADKEKITSLPTVTVTQEQVDMGLECPVCKEDYTVEEE
  VRQLPCNHFFHSSCIVPWLELHDTCPVCRKSLNGEDSTRQSQSTEASASNRFSNDSQLHD
  RWTF
• Function: E3 ubiquitin-protein ligase that catalyzes the 'Lys-48'- and/or 'Lys-63'-linked polyubiquitination of various substrates and thereby plays a role in a number of signaling pathways including autophagy, innate immunity, cell proliferation and cell death. Plays a role in the endosomal trafficking and degradation of membrane receptors including EGFR, FLT3, MET and CXCR4 through their polyubiquitination. Participates together with BST2 in antiviral immunity by facilitating the internalization of HIV-1 virions into intracellular vesicles leading to their lysosomal degradation. Possesses also an antiviral activity independently of BST2 by promoting retroviral GAG proteins ubiquitination, redistribution to endo-lysosomal compartments and, ultimately, lysosomal degradation. Catalyzes distinct types of ubiquitination on MAVS and STING1 at different phases of viral infection to promote innate antiviral response. Mediates the 'Lys-48'-linked ubiquitination of MAVS leading to its proteasomal degradation and ubiquitinates STING1 via 'Lys-63'-linked polyubiquitination, critical for its oligomerization and the subsequent recruitment of TBK1. Plays a positive role in the autophagosome-lysosome fusion by interacting with STX17 and enhancing its stability without affecting 'Lys-48'- or 'Lys-63'-linked polyubiquitination levels, which in turn promotes autophagosome maturation. Negatively regulates TLR-induced expression of proinflammatory cytokines by catalyzing 'Lys-11'-linked ubiquitination of RAB1A and RAB13 to inhibit post-ER trafficking of TLRs to the Golgi by RAB1A and subsequently from the Golgi apparatus to the cell surface by RAB13.
• Tissue Specificity: Expressed at extremely low levels in normal breast, prostate, lung, colon. Higher levels of expression are detected in heart, skeletal muscle, testis as well as in breast and prostate cancer cells.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[1]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[2]
Gout	DISHC0U7	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aminophenol	DMEMCQ9	Investigative	E3 ubiquitin-protein ligase RNF115 (RNF115) affects the response to substance of Aminophenol.	[15]

12 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 RNF115 (RNF115).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase RNF115 (RNF115).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of E3 ubiquitin-protein ligase RNF115 (RNF115).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF115 (RNF115).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase RNF115 (RNF115).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of E3 ubiquitin-protein ligase RNF115 (RNF115).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin-protein ligase RNF115 (RNF115).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of E3 ubiquitin-protein ligase RNF115 (RNF115).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of E3 ubiquitin-protein ligase RNF115 (RNF115).	[12]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of E3 ubiquitin-protein ligase RNF115 (RNF115).	[6]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of E3 ubiquitin-protein ligase RNF115 (RNF115).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase RNF115 (RNF115).	[14]

References

• [1] Deubiquitinase ubiquitin-specific protease 9X regulates the stability and function of E3 ubiquitin ligase ring finger protein 115 in breast cancer cells.Cancer Sci. 2019 Apr;110(4):1268-1278. doi: 10.1111/cas.13953. Epub 2019 Feb 21.
• [2] A novel RING-type ubiquitin ligase breast cancer-associated gene 2 correlates with outcome in invasive breast cancer.Cancer Res. 2005 Nov 15;65(22):10401-12. doi: 10.1158/0008-5472.CAN-05-2103.
• [3] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [13] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [14] 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.
• [15] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.