Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGXNB86)

• DOT Name: Innate immunity activator protein (INAVA)
• Gene Name: INAVA
• Related Disease:
  Alzheimer disease
  Anterior uveitis
  Breast cancer
  Breast carcinoma
  Coeliac disease
  Multiple sclerosis
  Inflammatory bowel disease
  Ankylosing spondylitis
  Crohn disease
  Psoriasis
  Sclerosing cholangitis
  Ulcerative colitis
• UniProt ID: INAVA_HUMAN
• Pfam ID: PF11819
• Sequence:
  MLQMPKLNEIPPGRAGRREARGEGRWPGQTGPEAARLEWRAQGQAGGARAPWDSWGSSRL
  PTQPGPGWSRCPPSLLCALSFQKSTMESKDEVSDTDSGIILQSGPDSPVSPMKELTHAVH
  KQQRALEARLEACLEELRRLCLREAELTGTLPAEYPLKPGEKAPKVRRRIGAAYKLDDWA
  LHREDPLSSLERQLALQLQITEAARRLCLEENLSRQARRQRKHSMLQEEKKLQELQRCLV
  ERRRNSEPPPAAALPLGRELSASDDSSLSDGLLLEEEESQVPKPPPESPAPPSRPLPPQT
  LEGLQPTGPEAGSPERAPVQNSPWKETSLDHPYEKPRKSSEPWSESSSPATTPQDGPSAS
  SLWLLEPASYHVVPIRGVPGQWQGRTSAPATPEIQGRRGQSQSLRVDSFRAGPEGRGRSA
  FPRRRPTHYTVTVPDSCFPATKPPLPHAACHSCSEDSGSDVSSISHPTSPGSSSPDISFL
  QPLSPPKTHRHRGAWVPAGSRELVAHHPKLLLPPGYFPAGRYVVVAESPLPPGEWELRRA
  APGPAYEEEGTPLRYQRLVPSRSRIVRTPSLKDSPAGRGLSKAAVSEELKWWHERARLRS
  TRPHSLDRQGAFRVRSLPLGREGFGRALGPRAQVPTVCVLRRSPDGAPVQVFVPEKGEII
  SQV
• Function: Expressed in peripheral macrophages and intestinal myeloid-derived cells, is required for optimal PRR (pattern recognition receptor)-induced signaling, cytokine secretion, and bacterial clearance. Upon stimulation of a broad range of PRRs (pattern recognition receptor) such as NOD2 or TLR2, TLR3, TLR4, TLR5, TLR7 and TLR9, associates with YWHAQ/14-3-3T, which in turn leads to the recruitment and activation of MAP kinases and NF-kappa-B signaling complexes that amplifies PRR-induced downstream signals and cytokine secretion. In the intestine, regulates adherens junction stability by regulating the degradation of CYTH1 and CYTH2, probably acting as substrate cofactor for SCF E3 ubiquitin-protein ligase complexes. Stabilizes adherens junctions by limiting CYTH1-dependent ARF6 activation.
• Tissue Specificity: Highly expressed in intestinal myeloid-derived cells and expressed in monocyte-derived macrophages upon induction by PRR activation.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Anterior uveitis	DISQ7EAD	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[4]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[5]
Inflammatory bowel disease	DISGN23E	moderate	Genetic Variation	[6]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[7]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[8]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[7]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[7]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Innate immunity activator protein (INAVA).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Innate immunity activator protein (INAVA).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Innate immunity activator protein (INAVA).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Innate immunity activator protein (INAVA).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Innate immunity activator protein (INAVA).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Innate immunity activator protein (INAVA).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Innate immunity activator protein (INAVA).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Innate immunity activator protein (INAVA).	[16]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Innate immunity activator protein (INAVA).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Innate immunity activator protein (INAVA).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Innate immunity activator protein (INAVA).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Innate immunity activator protein (INAVA).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Innate immunity activator protein (INAVA).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Innate immunity activator protein (INAVA).	[24]

2 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 decreases the methylation of Innate immunity activator protein (INAVA).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Innate immunity activator protein (INAVA).	[22]

References

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• [3] C1orf106, an innate immunity activator, is amplified in breast cancer and is required for basal-like/luminal progenitor fate decision.Sci China Life Sci. 2019 Sep;62(9):1229-1242. doi: 10.1007/s11427-019-9570-y. Epub 2019 Aug 1.
• [4] Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci.Eur J Hum Genet. 2016 Feb;24(2):291-7. doi: 10.1038/ejhg.2015.87. Epub 2015 Apr 29.
• [5] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [6] C1orf106 is a colitis risk gene that regulates stability of epithelial adherens junctions.Science. 2018 Mar 9;359(6380):1161-1166. doi: 10.1126/science.aan0814. Epub 2018 Feb 1.
• [7] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [8] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
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• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.