Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDQGI37)

• DOT Name: E3 ubiquitin-protein ligase RNF5 (RNF5)
• Synonyms: EC 2.3.2.27; RING finger protein 5; Ram1 homolog; HsRma1
• Gene Name: RNF5
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cystic fibrosis
  Depression
  Glioma
  Melanoma
  Membranous glomerulonephritis
  Multiple sclerosis
  Neoplasm
  Rheumatoid arthritis
  Type-1 diabetes
  Vitiligo
  Chronic obstructive pulmonary disease
  Hepatocellular carcinoma
  Pulmonary emphysema
  Bacterial infection
  Colitis
  Inflammatory bowel disease
  Streptococcus infection
  Systemic lupus erythematosus
• UniProt ID: RNF5_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13920
• Sequence:
  MAAAEEEDGGPEGPNRERGGAGATFECNICLETAREAVVSVCGHLYCWPCLHQWLETRPE
  RQECPVCKAGISREKVVPLYGRGSQKPQDPRLKTPPRPQGQRPAPESRGGFQPFGDTGGF
  HFSFGVGAFPFGFFTTVFNAHEPFRRGTGVDLGQGHPASSWQDSLFLFLAIFFFFWLLSI
• Function: Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins. May function together with E2 ubiquitin-conjugating enzymes UBE2D1/UBCH5A and UBE2D2/UBC4. Mediates ubiquitination of PXN/paxillin,thereby regulating cell motility and localization of PXN/paxillin. Catalyzes ubiquitination of Salmonella type III secreted protein sopA. Mediates the 'Lys-63'-linked polyubiquitination of JKAMP thereby regulating JKAMP function by decreasing its association with components of the proteasome and ERAD; the ubiquitination appears to involve E2 ubiquitin-conjugating enzyme UBE2N. Mediates the 'Lys-48'-linked polyubiquitination of STING1 at 'Lys-150' leading to its proteasomal degradation; the ubiquitination occurs in mitochondria after viral transfection and regulates antiviral responses. Catalyzes ubiquitination and subsequent degradation of ATG4B, thereby inhibiting autophagy.
• Tissue Specificity: Widely 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

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[2]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[3]
Depression	DIS3XJ69	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Melanoma	DIS1RRCY	Strong	Altered Expression	[2]
Membranous glomerulonephritis	DISFSUKQ	Strong	Genetic Variation	[5]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[8]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[9]
Vitiligo	DISR05SL	Strong	Genetic Variation	[10]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[12]
Pulmonary emphysema	DIS5M7HZ	moderate	Biomarker	[11]
Bacterial infection	DIS5QJ9S	Limited	Genetic Variation	[13]
Colitis	DISAF7DD	Limited	Biomarker	[14]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[15]
Streptococcus infection	DIS04U9T	Limited	Biomarker	[13]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase RNF5 (RNF5).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase RNF5 (RNF5).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF5 (RNF5).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase RNF5 (RNF5).	[20]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of E3 ubiquitin-protein ligase RNF5 (RNF5).	[21]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of E3 ubiquitin-protein ligase RNF5 (RNF5).	[17]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of E3 ubiquitin-protein ligase RNF5 (RNF5).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of E3 ubiquitin-protein ligase RNF5 (RNF5).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of E3 ubiquitin-protein ligase RNF5 (RNF5).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase RNF5 (RNF5).	[25]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of E3 ubiquitin-protein ligase RNF5 (RNF5).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of E3 ubiquitin-protein ligase RNF5 (RNF5).	[23]

References

• [1] Ubiquitin ligase RNF5 serves an important role in the development of human glioma.Oncol Lett. 2019 Nov;18(5):4659-4666. doi: 10.3892/ol.2019.10801. Epub 2019 Sep 4.
• [2] Increased expression of the E3 ubiquitin ligase RNF5 is associated with decreased survival in breast cancer.Cancer Res. 2007 Sep 1;67(17):8172-9. doi: 10.1158/0008-5472.CAN-07-0045.
• [3] Pharmacological Inhibition of the Ubiquitin Ligase RNF5 Rescues F508del-CFTR in Cystic Fibrosis Airway Epithelia.Cell Chem Biol. 2018 Jul 19;25(7):891-905.e8. doi: 10.1016/j.chembiol.2018.04.010. Epub 2018 May 10.
• [4] Involvement of hippocampal angiotensin 1 receptors in anxiety-like behaviour of olfactory bulbectomized rats.Pharmacol Rep. 2018 Oct;70(5):847-852. doi: 10.1016/j.pharep.2018.03.001. Epub 2018 Mar 8.
• [5] Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy.N Engl J Med. 2011 Feb 17;364(7):616-26. doi: 10.1056/NEJMoa1009742.
• [6] Evidence for VAV2 and ZNF433 as susceptibility genes for multiple sclerosis.J Neuroimmunol. 2010 Oct 8;227(1-2):162-6. doi: 10.1016/j.jneuroim.2010.06.003. Epub 2010 Jul 2.
• [7] Triple-layer dissection of the lung adenocarcinoma transcriptome: regulation at the gene, transcript, and exon levels.Oncotarget. 2015 Oct 6;6(30):28755-73. doi: 10.18632/oncotarget.4810.
• [8] A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis.Ann Rheum Dis. 2011 Feb;70(2):259-65. doi: 10.1136/ard.2009.126821. Epub 2010 Dec 14.
• [9] A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.Nature. 2007 Aug 2;448(7153):591-4. doi: 10.1038/nature06010. Epub 2007 Jul 15.
• [10] 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.
• [11] Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema.J Mol Med (Berl). 2011 Jun;89(6):577-93. doi: 10.1007/s00109-011-0732-8. Epub 2011 Feb 12.
• [12] Six genes as potential diagnosis and prognosis biomarkers for hepatocellular carcinoma through data mining.J Cell Physiol. 2019 Jun;234(6):9787-9792. doi: 10.1002/jcp.27664. Epub 2018 Dec 17.
• [13] Regulation of ATG4B stability by RNF5 limits basal levels of autophagy and influences susceptibility to bacterial infection.PLoS Genet. 2012;8(10):e1003007. doi: 10.1371/journal.pgen.1003007. Epub 2012 Oct 18.
• [14] Preparation of Chondroitin Sulfate-Glycyl-Prednisolone Conjugate Nanogel and Its Efficacy in Rats with Ulcerative Colitis.Biol Pharm Bull. 2019;42(7):1155-1163. doi: 10.1248/bpb.b19-00020.
• [15] Regulation of S100A8 Stability by RNF5 in Intestinal Epithelial Cells Determines Intestinal Inflammation and Severity of Colitis.Cell Rep. 2018 Sep 18;24(12):3296-3311.e6. doi: 10.1016/j.celrep.2018.08.057.
• [16] 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.
• [17] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [18] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Progestins regulate genes that can elicit both proliferative and antiproliferative effects in breast cancer cells. Oncol Rep. 2008 Jun;19(6):1627-34.
• [22] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [23] 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.
• [24] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [25] 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.