Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9W9DE0)

• DOT Name: Interleukin-17F (IL17F)
• Synonyms: IL-17F; Cytokine ML-1
• Gene Name: IL17F
• Related Disease:
  Chronic mucocutaneous candidiasis
  Candidiasis, familial, 6
• UniProt ID: IL17F_HUMAN
• PDB ID: 1JPY; 3JVF; 5N92; 5NAN; 6HG4; 6HG9; 6HGO; 6PPG
• Pfam ID: PF06083
• Sequence:
  MTVKTLHGPAMVKYLLLSILGLAFLSEAAARKIPKVGHTFFQKPESCPPVPGGSMKLDIG
  IINENQRVSMSRNIESRSTSPWNYTVTWDPNRYPSEVVQAQCRNLGCINAQGKEDISMNS
  VPIQQETLVVRRKHQGCSVSFQLEKVLVTVGCTCVTPVIHHVQ
• Function: Effector cytokine of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity. IL17A-IL17F signals via IL17RA-IL17RC heterodimeric receptor complex, triggering homotypic interaction of IL17RA and IL17RC chains with TRAF3IP2 adapter through SEFIR domains. This leads to downstream TRAF6-mediated activation of NF-kappa-B and MAPkinase pathways ultimately resulting in transcriptional activation of cytokines, chemokines, antimicrobial peptides and matrix metalloproteinases, with potential strong immune inflammation. IL17A-IL17F is primarily involved in host defense against extracellular bacteria and fungi by inducing neutrophilic inflammation. As signature effector cytokine of T-helper 17 cells (Th17), primarily induces neutrophil activation and recruitment at infection and inflammatory sites. Stimulates the production of antimicrobial beta-defensins DEFB1, DEFB103A, and DEFB104A by mucosal epithelial cells, limiting the entry of microbes through the epithelial barriers. IL17F homodimer can signal via IL17RC homodimeric receptor complex, triggering downstream activation of TRAF6 and NF-kappa-B signaling pathway. Via IL17RC induces transcriptional activation of IL33, a potent cytokine that stimulates group 2 innate lymphoid cells and adaptive T-helper 2 cells involved in pulmonary allergic response to fungi. Likely via IL17RC, promotes sympathetic innervation of peripheral organs by coordinating the communication between gamma-delta T cells and parenchymal cells. Stimulates sympathetic innervation of thermogenic adipose tissue by driving TGFB1 expression. Regulates the composition of intestinal microbiota and immune tolerance by inducing antimicrobial proteins that specifically control the growth of commensal Firmicutes and Bacteroidetes.
• Tissue Specificity: Expressed in T-helper 1 and T-helper 2 cells, basophils and mast cells.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  IL-17 sig.ling pathway (hsa04657)
  Th17 cell differentiation (hsa04659)
  Inflammatory bowel disease (hsa05321)
• Reactome Pathway:
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Interleukin-17 signaling (R-HSA-448424)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic mucocutaneous candidiasis	DISPSGYF	Supportive	Autosomal dominant	[1]
Candidiasis, familial, 6	DISIPVY7	Limited	Unknown	[1]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Simvastatin	DM30SGU	Approved	Simvastatin decreases the secretion of Interleukin-17F (IL17F).	[2]

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 Interleukin-17F (IL17F).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-17F (IL17F).	[4]

References

• [1] Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science. 2011 Apr 1;332(6025):65-8. doi: 10.1126/science.1200439. Epub 2011 Feb 24.
• [2] Simvastatin inhibits IFN regulatory factor 4 expression and Th17 cell differentiation in CD4+ T cells derived from patients with multiple sclerosis. J Immunol. 2011 Sep 15;187(6):3431-7. doi: 10.4049/jimmunol.1100580. Epub 2011 Aug 19.
• [3] 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.
• [4] Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression. Cell Rep. 2015 Sep 29;12(12):1986-96. doi: 10.1016/j.celrep.2015.08.046. Epub 2015 Sep 17.