Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJX1YC7)

• DOT Name: Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT)
• Synonyms: Protein SITPEC
• Gene Name: ECSIT
• Related Disease:
  Alzheimer disease
  T-cell lymphoma
  Bacterial infection
• UniProt ID: ECSIT_HUMAN
• Pfam ID: PF14784 ; PF06239
• Sequence:
  MSWVQATLLARGLCRAWGGTCGAALTGTSISQVPRRLPRGLHCSAAAHSSEQSLVPSPPE
  PRQRPTKALVPFEDLFGQAPGGERDKASFLQTVQKFAEHSVRKRGHIDFIYLALRKMREY
  GVERDLAVYNQLLNIFPKEVFRPRNIIQRIFVHYPRQQECGIAVLEQMENHGVMPNKETE
  FLLIQIFGRKSYPMLKLVRLKLWFPRFMNVNPFPVPRDLPQDPVELAMFGLRHMEPDLSA
  RVTIYQVPLPKDSTGAADPPQPHIVGIQSPDQQAALARHNPARPVFVEGPFSLWLRNKCV
  YYHILRADLLPPEEREVEETPEEWNLYYPMQLDLEYVRSGWDNYEFDINEVEEGPVFAMC
  MAGAHDQATMAKWIQGLQETNPTLAQIPVVFRLAGSTRELQTSSAGLEEPPLPEDHQEED
  DNLQRQQQGQS
• Function: Adapter protein that plays a role in different signaling pathways including TLRs and IL-1 pathways or innate antiviral induction signaling. Plays a role in the activation of NF-kappa-B by forming a signal complex with TRAF6 and TAK1/MAP3K7 to activate TAK1/MAP3K7 leading to activation of IKKs. Once ubiquitinated, interacts with the dissociated RELA and NFKB1 proteins and translocates to the nucleus where it induces NF-kappa-B-dependent gene expression. Plays a role in innate antiviral immune response by bridging the pattern recognition receptors RIGI and MDA5/IFIT1 to the MAVS complex at the mitochondrion. Promotes proteolytic activation of MAP3K1. Involved in the BMP signaling pathway. Required for normal embryonic development; As part of the MCIA complex, involved in the assembly of the mitochondrial complex I.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)
• Reactome Pathway:
  Complex I biogenesis (R-HSA-6799198)
  TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (R-HSA-975138)
  MyD88 cascade initiated on plasma membrane (R-HSA-975871)
  MyD88 (R-HSA-166058)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
T-cell lymphoma	DISSXRTQ	Strong	Genetic Variation	[2]
Bacterial infection	DIS5QJ9S	moderate	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT).	[6]
Selenium	DM25CGV	Approved	Selenium increases the expression of Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT).	[7]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT).	[10]

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 decreases the methylation of Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT).	[9]

References

• [1] Interactome mapping suggests new mechanistic details underlying Alzheimer's disease.Genome Res. 2011 Mar;21(3):364-76. doi: 10.1101/gr.114280.110. Epub 2010 Dec 16.
• [2] Recurrent ECSIT mutation encoding V140A triggers hyperinflammation and promotes hemophagocytic syndrome in extranodal NK/T cell lymphoma.Nat Med. 2018 Feb;24(2):154-164. doi: 10.1038/nm.4456. Epub 2018 Jan 1.
• [3] Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity.Nat Immunol. 2015 Nov;16(11):1142-52. doi: 10.1038/ni.3268. Epub 2015 Sep 28.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] 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.
• [8] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [9] 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.
• [10] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.