Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYFTPS0)

• DOT Name: NF-kappa-B inhibitor-like protein 1 (NFKBIL1)
• Synonyms: Inhibitor of kappa B-like protein; I-kappa-B-like protein; IkappaBL; Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-like 1
• Gene Name: NFKBIL1
• Related Disease:
  Autism
  Hepatitis C virus infection
  Idiopathic inflammatory myopathy
  Influenza
  Language disorder
  Leprosy
  Myasthenia gravis
  Non-hodgkin lymphoma
  Non-insulin dependent diabetes
  Periodontal disease
  Periodontitis
  Psoriasis
  Sjogren syndrome
  Systemic lupus erythematosus
  Ulcerative colitis
  Autoimmune disease
  Myocardial infarction
  Type-1 diabetes
  Arthritis
  Crohn disease
  Pulmonary tuberculosis
  Rheumatoid arthritis
  Tuberculosis
• UniProt ID: IKBL1_HUMAN
• Pfam ID: PF13637
• Sequence:
  MSNPSPQVPEEEASTSVCRPKSSMASTSRRQRRERRFRRYLSAGRLVRAQALLQRHPGLD
  VDAGQPPPLHRACARHDAPALCLLLRLGADPAHQDRHGDTALHAAARQGPDAYTDFFLPL
  LSRCPSAMGIKNKDGETPGQILGWGPPWDSAEEEEEDDASKEREWRQKLQGELEDEWQEV
  MGRFEGDASHETQEPESFSAWSDRLAREHAQKCQQQQREAEGSRRPPRAEGSSQSWRQQE
  EEQRLFRERARAKEEELRESRARRAQEALGDREPKPTRAGPREEHPRGAGRGSLWRFGDV
  PWPCPGGGDPEAMAAALVARGPPLEEQGALRRYLRVQQVRWHPDRFLQRFRSQIETWELG
  RVMGAVTALSQALNRHAEALK
• Function: Involved in the regulation of innate immune response. Acts as negative regulator of Toll-like receptor and interferon-regulatory factor (IRF) signaling pathways. Contributes to the negative regulation of transcriptional activation of NF-kappa-B target genes in response to endogenous proinflammatory stimuli.
• Tissue Specificity: Detected in different cell types including monocytes, T-cells, B-cells and hepatocytes.

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Genetic Variation	[1]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[2]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Biomarker	[3]
Influenza	DIS3PNU3	Strong	Biomarker	[4]
Language disorder	DISTLKP7	Strong	Genetic Variation	[1]
Leprosy	DISAA4UI	Strong	Biomarker	[5]
Myasthenia gravis	DISELRCI	Strong	Genetic Variation	[6]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[7]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[8]
Periodontal disease	DISJQHVN	Strong	Biomarker	[9]
Periodontitis	DISI9JOI	Strong	Genetic Variation	[10]
Psoriasis	DIS59VMN	Strong	Biomarker	[11]
Sjogren syndrome	DISUBX7H	Strong	Genetic Variation	[12]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[13]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[14]
Autoimmune disease	DISORMTM	moderate	Genetic Variation	[4]
Myocardial infarction	DIS655KI	moderate	Genetic Variation	[15]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[16]
Arthritis	DIST1YEL	Disputed	Biomarker	[17]
Crohn disease	DIS2C5Q8	Disputed	Genetic Variation	[18]
Pulmonary tuberculosis	DIS6FLUM	Limited	Genetic Variation	[19]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[20]
Tuberculosis	DIS2YIMD	Limited	Genetic Variation	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of NF-kappa-B inhibitor-like protein 1 (NFKBIL1).	[21]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NF-kappa-B inhibitor-like protein 1 (NFKBIL1).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NF-kappa-B inhibitor-like protein 1 (NFKBIL1).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of NF-kappa-B inhibitor-like protein 1 (NFKBIL1).	[24]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of NF-kappa-B inhibitor-like protein 1 (NFKBIL1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NF-kappa-B inhibitor-like protein 1 (NFKBIL1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of NF-kappa-B inhibitor-like protein 1 (NFKBIL1).	[27]

References

• [1] Associations between autistic-like traits and polymorphisms in NFKBIL1.Acta Neuropsychiatr. 2019 Aug;31(4):220-229. doi: 10.1017/neu.2019.18. Epub 2019 Jun 4.
• [2] The haplotype block, NFKBIL1-ATP6V1G2-BAT1-MICB-MICA, within the class III-class I boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus-associated dilated cardiomyopathy.Tissue Antigens. 2005 Sep;66(3):200-8. doi: 10.1111/j.1399-0039.2005.00457.x.
• [3] Genetic association study of NF-B genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopathy.Rheumatology (Oxford). 2012 May;51(5):794-9. doi: 10.1093/rheumatology/ker379. Epub 2011 Dec 30.
• [4] A novel link of HLA locus to the regulation of immunity and infection: NFKBIL1 regulates alternative splicing of human immune-related genes and influenza virus M gene.J Autoimmun. 2013 Dec;47:25-33. doi: 10.1016/j.jaut.2013.07.010. Epub 2013 Aug 14.
• [5] PARK2 and proinflammatory/anti-inflammatory cytokine gene interactions contribute to the susceptibility to leprosy: a case-control study of North Indian population.BMJ Open. 2014 Feb 27;4(2):e004239. doi: 10.1136/bmjopen-2013-004239.
• [6] Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations.Mol Med. 2016 Mar;21(1):769-781. doi: 10.2119/molmed.2015.00232. Epub 2015 Nov 10.
• [7] Common gene variants in the tumor necrosis factor (TNF) and TNF receptor superfamilies and NF-kB transcription factors and non-Hodgkin lymphoma risk.PLoS One. 2009;4(4):e5360. doi: 10.1371/journal.pone.0005360. Epub 2009 Apr 24.
• [8] Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes.Nat Commun. 2018 Jul 27;9(1):2941. doi: 10.1038/s41467-018-04951-w.
• [9] Salivary biomarkers in association with periodontal parameters and the periodontitis risk haplotype.Innate Immun. 2018 Oct;24(7):439-447. doi: 10.1177/1753425918796207. Epub 2018 Sep 3.
• [10] Genetic variation on the BAT1-NFKBIL1-LTA region of major histocompatibility complex class III associates with periodontitis. Infect Immun. 2014 May;82(5):1939-48.
• [11] Association with Genetic Variants in the IL-23 and NF-B Pathways Discriminates between Mild and Severe Psoriasis Skin Disease.J Invest Dermatol. 2015 Aug;135(8):1969-1976. doi: 10.1038/jid.2015.103. Epub 2015 Mar 19.
• [12] The IkappaBL gene polymorphism influences risk of acquiring systemic lupus erythematosus and Sjgren's syndrome.Hum Immunol. 2008 Jan;69(1):45-51. doi: 10.1016/j.humimm.2007.11.008. Epub 2007 Dec 26.
• [13] 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.
• [14] Characteristics of Japanese inflammatory bowel disease susceptibility loci.J Gastroenterol. 2014 Aug;49(8):1217-30. doi: 10.1007/s00535-013-0866-2. Epub 2013 Aug 13.
• [15] Association of variants in the BAT1-NFKBIL1-LTA genomic region with protection against myocardial infarction in Europeans.Hum Mol Genet. 2007 Aug 1;16(15):1821-7. doi: 10.1093/hmg/ddm130. Epub 2007 May 21.
• [16] IKBL promoter polymorphism is strongly associated with resistance to type 1 diabetes in Japanese.Tissue Antigens. 2004 Mar;63(3):223-30. doi: 10.1111/j.0001-2815.2004.00164.x.
• [17] NFKBIL1 confers resistance to experimental autoimmune arthritis through the regulation of dendritic cell functions.Scand J Immunol. 2011 May;73(5):478-85. doi: 10.1111/j.1365-3083.2011.02524.x.
• [18] Role of the NFKB1 -94ins/delATTG promoter polymorphism in IBD and potential interactions with polymorphisms in the CARD15/NOD2, IKBL, and IL-1RN genes.Inflamm Bowel Dis. 2006 Jul;12(7):606-11. doi: 10.1097/01.ibd.0000225346.23765.6b.
• [19] Analysis of IL1B, TAP1, TAP2 and IKBL polymorphisms on susceptibility to tuberculosis.Tissue Antigens. 2006 Apr;67(4):290-6. doi: 10.1111/j.1399-0039.2006.00566.x.
• [20] 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.
• [21] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [22] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [23] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [24] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [25] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [26] 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.
• [27] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.