Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8YSNI4)

• DOT Name: Interferon regulatory factor 8 (IRF8)
• Synonyms: IRF-8; Interferon consensus sequence-binding protein; H-ICSBP; ICSBP
• Gene Name: IRF8
• Related Disease:
  Immunodeficiency 32B
  Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency
• UniProt ID: IRF8_HUMAN
• Pfam ID: PF00605 ; PF10401
• Sequence:
  MCDRNGGRRLRQWLIEQIDSSMYPGLIWENEEKSMFRIPWKHAGKQDYNQEVDASIFKAW
  AVFKGKFKEGDKAEPATWKTRLRCALNKSPDFEEVTDRSQLDISEPYKVYRIVPEEEQKC
  KLGVATAGCVNEVTEMECGRSEIDELIKEPSVDDYMGMIKRSPSPPEACRSQLLPDWWAQ
  QPSTGVPLVTGYTTYDAHHSAFSQMVISFYYGGKLVGQATTTCPEGCRLSLSQPGLPGTK
  LYGPEGLELVRFPPADAIPSERQRQVTRKLFGHLERGVLLHSSRQGVFVKRLCQGRVFCS
  GNAVVCKGRPNKLERDEVVQVFDTSQFFRELQQFYNSQGRLPDGRVVLCFGEEFPDMAPL
  RSKLILVQIEQLYVRQLAEEAGKSCGAGSVMQAPEEPPPDQVFRMFPDICASHQRSFFRE
  NQQITV
• Function: Transcription factor that specifically binds to the upstream regulatory region of type I interferon (IFN) and IFN-inducible MHC class I genes (the interferon consensus sequence (ICS)). Can both act as a transcriptional activator or repressor. Plays a negative regulatory role in cells of the immune system. Involved in CD8(+) dendritic cell differentiation by forming a complex with the BATF-JUNB heterodimer in immune cells, leading to recognition of AICE sequence (5'-TGAnTCA/GAAA-3'), an immune-specific regulatory element, followed by cooperative binding of BATF and IRF8 and activation of genes. Required for the development of plasmacytoid dendritic cells (pDCs), which produce most of the type I IFN in response to viral infection. Positively regulates macroautophagy in dendritic cells. Acts as a transcriptional repressor of osteoclast differentiation factors such as NFATC1 and EEIG1.
• Tissue Specificity: Predominantly expressed in lymphoid tissues.
• KEGG Pathway: Pertussis (hsa05133)
• Reactome Pathway:
  Interferon alpha/beta signaling (R-HSA-909733)
  Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency 32B	DISCMFL6	Strong	Autosomal recessive	[1]
Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency	DISYJ29X	Strong	Autosomal dominant	[1]

11 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 Interferon regulatory factor 8 (IRF8).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Interferon regulatory factor 8 (IRF8).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Interferon regulatory factor 8 (IRF8).	[4]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Interferon regulatory factor 8 (IRF8).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Interferon regulatory factor 8 (IRF8).	[7]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Interferon regulatory factor 8 (IRF8).	[8]
Fenfluramine	DM0762O	Phase 3	Fenfluramine increases the expression of Interferon regulatory factor 8 (IRF8).	[9]
MK-2206	DMT1OZ6	Phase 2	MK-2206 decreases the expression of Interferon regulatory factor 8 (IRF8).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Interferon regulatory factor 8 (IRF8).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interferon regulatory factor 8 (IRF8).	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Interferon regulatory factor 8 (IRF8).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Interferon regulatory factor 8 (IRF8).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Interferon regulatory factor 8 (IRF8).	[13]

References

• [1] IRF8 mutations and human dendritic-cell immunodeficiency. N Engl J Med. 2011 Jul 14;365(2):127-38. doi: 10.1056/NEJMoa1100066. Epub 2011 Apr 27.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] 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.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [6] 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.
• [7] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [8] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [9] Fenfluramine-induced gene dysregulation in human pulmonary artery smooth muscle and endothelial cells. Pulm Circ. 2011 Jul-Sep;1(3):405-18. doi: 10.4103/2045-8932.87310.
• [10] Chemerin promotes the pathogenesis of preeclampsia by activating CMKLR1/p-Akt/CEBP axis and inducing M1 macrophage polarization. Cell Biol Toxicol. 2022 Aug;38(4):611-628. doi: 10.1007/s10565-021-09636-7. Epub 2021 Aug 16.
• [11] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [12] Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell. 2013 Dec 9;24(6):777-90. doi: 10.1016/j.ccr.2013.11.003.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [14] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.