Details of Drug Off-Target (DOT)

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

• DOT Name: Interleukin-17 receptor C (IL17RC)
• Synonyms: IL-17 receptor C; IL-17RC; Interleukin-17 receptor homolog; IL17Rhom; Interleukin-17 receptor-like protein; IL-17RL; ZcytoR14
• Gene Name: IL17RC
• Related Disease:
  Multiple sclerosis
  Acute graft versus host disease
  Adult respiratory distress syndrome
  Advanced cancer
  Age-related macular degeneration
  Androgen insensitivity syndrome
  Bullous pemphigoid
  Capillary malformation
  Non-small-cell lung cancer
  Polyp
  Prostate cancer
  Prostate carcinoma
  Psoriasis
  Ulcerative colitis
  Chronic obstructive pulmonary disease
  Keratitis
  Neoplasm
  Chronic mucocutaneous candidiasis
  Bladder cancer
  Candidiasis, familial, 9
  Colorectal carcinoma
  Nervous system inflammation
  Prostate neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: I17RC_HUMAN
• PDB ID: 6HG4; 6HG9; 6HGA; 7UWN; 7ZAN
• Pfam ID: PF15037 ; PF08357
• Sequence:
  MPVPWFLLSLALGRSPVVLSLERLVGPQDATHCSPVSLEPWGDEERLRVQFLAQQSLSLA
  PVTAATARTALSGLSGADGRREERGRGKSWVCLSLGGSGNTEPQKKGLSCRLWDSDILCL
  PGDIVPAPGPVLAPTHLQTELVLRCQKETDCDLCLRVAVHLAVHGHWEEPEDEEKFGGAA
  DSGVEEPRNASLQAQVVLSFQAYPTARCVLLEVQVPAALVQFGQSVGSVVYDCFEAALGS
  EVRIWSYTQPRYEKELNHTQQLPDCRGLEVWNSIPSCWALPWLNVSADGDNVHLVLNVSE
  EQHFGLSLYWNQVQGPPKPRWHKNLTGPQIITLNHTDLVPCLCIQVWPLEPDSVRTNICP
  FREDPRAHQNLWQAARLQLLTLQSWLLDAPCSLPAEAALCWRAPGGDPCQPLVPPLSWEN
  VTVDKVLEFPLLKGHPNLCVQVNSSEKLQLQECLWADSLGPLKDDVLLLETRGPQDNRSL
  CALEPSGCTSLPSKASTRAARLGEYLLQDLQSGQCLQLWDDDLGALWACPMDKYIHKRWA
  LVWLACLLFAAALSLILLLKKDHAKGWLRLLKQDVRSGAAARGRAALLLYSADDSGFERL
  VGALASALCQLPLRVAVDLWSRRELSAQGPVAWFHAQRRQTLQEGGVVVLLFSPGAVALC
  SEWLQDGVSGPGAHGPHDAFRASLSCVLPDFLQGRAPGSYVGACFDRLLHPDAVPALFRT
  VPVFTLPSQLPDFLGALQQPRAPRSGRLQERAEQVSRALQPALDSYFHPPGTPAPGRGVG
  PGAGPGAGDGT
• Function: Receptor for IL17A and IL17F, major effector cytokines of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity. Receptor for IL17A and IL17F, major effector cytokines of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity. Receptor for IL17A and IL17F homodimers as part of a heterodimeric complex with IL17RA. Receptor for the heterodimer formed by IL17A and IL17B as part of a heterodimeric complex with IL17RA. Has also been shown to be the cognate receptor for IL17F and to bind IL17A with high affinity without the need for IL17RA. Upon binding of IL17F homodimer triggers downstream activation of TRAF6 and NF-kappa-B signaling pathway. 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. 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. Binding of IL17A-IL17F to IL17RA-IL17RC heterodimeric receptor complex triggers 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. 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; [Isoform 5]: Receptor for both IL17A and IL17F; [Isoform 6]: Does not bind IL17A or IL17F; [Isoform 7]: Does not bind IL17A or IL17F; [Isoform 8]: Receptor for both IL17A and IL17F.
• Tissue Specificity: Expressed in prostate, skeletal muscle, kidney and placenta (at protein level) . Expressed in brain, cartilage, colon, heart, intestine, kidney, liver, lung, muscle, placenta, and prostate . Also detected in thyroid, trachea and adrenal gland . Low expression in thymus and leukocytes .
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  IL-17 sig.ling pathway (hsa04657)
  Alcoholic liver disease (hsa04936)
• Reactome Pathway:
  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

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Altered Expression	[1]
Acute graft versus host disease	DIS8KLVM	Strong	Biomarker	[2]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Age-related macular degeneration	DIS0XS2C	Strong	Biomarker	[5]
Androgen insensitivity syndrome	DISUZBBO	Strong	Genetic Variation	[6]
Bullous pemphigoid	DISOJLKV	Strong	Altered Expression	[7]
Capillary malformation	DISR6ZSG	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Polyp	DISRSLYF	Strong	Biomarker	[9]
Prostate cancer	DISF190Y	Strong	Altered Expression	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Psoriasis	DIS59VMN	Strong	Altered Expression	[11]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[9]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[12]
Keratitis	DISMFOEI	moderate	Biomarker	[13]
Neoplasm	DISZKGEW	moderate	Biomarker	[14]
Chronic mucocutaneous candidiasis	DISPSGYF	Supportive	Autosomal dominant	[15]
Bladder cancer	DISUHNM0	Limited	Biomarker	[16]
Candidiasis, familial, 9	DIS9SQJM	Limited	Unknown	[17]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[18]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[19]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[10]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[16]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Interleukin-17 receptor C (IL17RC).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Interleukin-17 receptor C (IL17RC).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interleukin-17 receptor C (IL17RC).	[22]
Selenium	DM25CGV	Approved	Selenium increases the expression of Interleukin-17 receptor C (IL17RC).	[23]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Interleukin-17 receptor C (IL17RC).	[24]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Interleukin-17 receptor C (IL17RC).	[25]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Interleukin-17 receptor C (IL17RC).	[26]

References

• [1] Reassessment of blood gene expression markers for the prognosis of relapsing-remitting multiple sclerosis.PLoS One. 2011;6(12):e29648. doi: 10.1371/journal.pone.0029648. Epub 2011 Dec 27.
• [2] Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome.Blood. 2017 Apr 13;129(15):2172-2185. doi: 10.1182/blood-2016-08-732628. Epub 2017 Jan 30.
• [3] Vasoactive intestinal peptide inhibits the activation of murine fibroblasts and expression of interleukin 17 receptor C.Cell Biol Int. 2019 Jul;43(7):770-780. doi: 10.1002/cbin.11151. Epub 2019 May 18.
• [4] Chronic mucocutaneous candidiasis: what can we conclude about IL-17 antagonism?.J Dermatolog Treat. 2018 Aug;29(5):475-480. doi: 10.1080/09546634.2017.1398396. Epub 2017 Nov 21.
• [5] Interleukin-17 retinotoxicity is prevented by gene transfer of a soluble interleukin-17 receptor acting as a cytokine blocker: implications for age-related macular degeneration.PLoS One. 2014 Apr 29;9(4):e95900. doi: 10.1371/journal.pone.0095900. eCollection 2014.
• [6] A single-nucleotide polymorphism rs708567 in the IL-17RC gene is associated with a susceptibility to and the curve severity of adolescent idiopathic scoliosis in a Chinese Han population: a case-control study.BMC Musculoskelet Disord. 2012 Sep 21;13:181. doi: 10.1186/1471-2474-13-181.
• [7] Characteristic Pattern of IL-17RA, IL-17RB, and IL-17RC in Monocytes/Macrophages and Mast Cells From Patients With Bullous Pemphigoid.Front Immunol. 2019 Sep 11;10:2107. doi: 10.3389/fimmu.2019.02107. eCollection 2019.
• [8] Expression of IL-17A, E, and F and their receptors in non-small-cell lung cancer.J Biol Regul Homeost Agents. 2018 Sep-Oct;32(5):1105-1116.
• [9] Expression and location of IL-17A, E, F and their receptors in colorectal adenocarcinoma: Comparison with benign intestinal disease.Pathol Res Pract. 2018 Apr;214(4):482-491. doi: 10.1016/j.prp.2018.03.011. Epub 2018 Mar 7.
• [10] Differential expression of IL-17RC isoforms in androgen-dependent and androgen-independent prostate cancers.Neoplasia. 2007 Jun;9(6):464-70. doi: 10.1593/neo.07109.
• [11] Ultraviolet B Inhibits IL-17A/TNF--Stimulated Activation of Human Dermal Fibroblasts by Decreasing the Expression of IL-17RA and IL-17RC on Fibroblasts.Front Immunol. 2017 Feb 3;8:91. doi: 10.3389/fimmu.2017.00091. eCollection 2017.
• [12] Increased IL-17RA and IL-17RC in End-Stage COPD and the Contribution to Mast Cell Secretion of FGF-2 and VEGF.Respir Res. 2017 Mar 15;18(1):48. doi: 10.1186/s12931-017-0534-9.
• [13] IL-17 Promotes Pseudomonas aeruginosa Keratitis in C57BL/6 Mouse Corneas.J Immunol. 2020 Jan 1;204(1):169-179. doi: 10.4049/jimmunol.1900736. Epub 2019 Nov 25.
• [14] IL-17A-Induced PLET1 Expression Contributes to Tissue Repair and Colon Tumorigenesis.J Immunol. 2017 Dec 1;199(11):3849-3857. doi: 10.4049/jimmunol.1601540. Epub 2017 Oct 25.
• [15] Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis. J Exp Med. 2015 May 4;212(5):619-31. doi: 10.1084/jem.20141065. Epub 2015 Apr 27.
• [16] Immune analysis of expression of IL-17 relative ligands and their receptors in bladder cancer: comparison with polyp and cystitis.BMC Immunol. 2016 Oct 3;17(1):36. doi: 10.1186/s12865-016-0174-8.
• [17] IL-17RC is required for immune signaling via an extended SEF/IL-17R signaling domain in the cytoplasmic tail. J Immunol. 2010 Jul 15;185(2):1063-70. doi: 10.4049/jimmunol.0903739. Epub 2010 Jun 16.
• [18] IL-17R deletion predicts high-grade colorectal cancer and poor clinical outcomes.Int J Cancer. 2019 Jul 15;145(2):548-558. doi: 10.1002/ijc.32122. Epub 2019 Jan 28.
• [19] IL-17RC is required for IL-17A- and IL-17F-dependent signaling and the pathogenesis of experimental autoimmune encephalomyelitis.J Immunol. 2010 Apr 15;184(8):4307-16. doi: 10.4049/jimmunol.0903614. Epub 2010 Mar 15.
• [20] 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.
• [21] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [22] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [23] 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.
• [24] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [25] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [26] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.