Interleukin-17 receptor
Identifiers
SymbolIL17R
PfamPF08357
InterProIPR013568
Membranome8
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
interleukin 17 receptor A
Crystal structure of a complex of IL-17RA bound to IL-17F in a 1:2 stoichiometry.[1]
Identifiers
SymbolIL17RA
Alt. symbolsIL17R, CDw217
NCBI gene23765
HGNC5985
OMIM605461
RefSeqNM_014339
UniProtQ96F46
Other data
LocusChr. 22 q11.1
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StructuresSwiss-model
DomainsInterPro
interleukin 17 receptor B
Identifiers
SymbolIL17RB
Alt. symbolsIL17BR
NCBI gene55540
HGNC18015
OMIM605458
RefSeqNM_172234
UniProtQ9NRM6
Other data
LocusChr. 3 p21.1
Search for
StructuresSwiss-model
DomainsInterPro
interleukin 17 receptor C
Identifiers
SymbolIL17RC
Alt. symbolsIL17-RL
NCBI gene84818
HGNC18358
OMIM610925
RefSeqNM_032732
UniProtQ8NAC3
Other data
LocusChr. 3 p25.3
Search for
StructuresSwiss-model
DomainsInterPro
Interleukin 17 receptor D
Identifiers
SymbolIL17RD
Alt. symbolsSEF, IL17RLM, FLJ35755, IL-17RD
NCBI gene54756
HGNC17616
OMIM606807
RefSeqNM_017563
UniProtQ8NFM7
Other data
LocusChr. 3 p21.1
Search for
StructuresSwiss-model
DomainsInterPro
interleukin 17 receptor E
Identifiers
SymbolIL17RE
Alt. symbolsFLJ23658
NCBI gene132014
HGNC18439
RefSeqNM_153480
UniProtQ8NFR9
Other data
LocusChr. 3 p25.3
Search for
StructuresSwiss-model
DomainsInterPro
Interleukin 17 receptor E-like
Identifiers
SymbolIL17REL
NCBI gene400935
HGNC33808
RefSeqNM_001001694
UniProtQ6ZVW7
Other data
LocusChr. 22 q13.33
Search for
StructuresSwiss-model
DomainsInterPro

Interleukin-17 receptor (IL-17R) is a cytokine receptor which belongs to new subfamily of receptors binding proinflammatory cytokine interleukin 17A, a member of IL-17 family ligands produced by T helper 17 cells (Th17).[2] IL-17R family consists of 5 members: IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE. Functional IL-17R is a transmembrane receptor complex usually consisting of one IL-17RA, which is a founding member of the family, and second other family subunit, thus forming heteromeric receptor binding different ligands. IL-17A, a founding member of IL-17 ligand family binds to heteromeric IL-17RA/RC receptor complex.[3] IL-17RB binds preferentially IL-17B and IL-17E[4][5] and heteromeric IL-17RA/RE complex binds IL-17C. However, there is still unknown ligand for IL-17RD. The first identified member IL-17RA is located on human chromosome 22, whereas other subunits IL-17RB to IL-17RD are encoded within human chromosome 3.

Evolution

IL17RD is probably the most ancient member of IL-17 receptor family. It was firstly identified in zebrafish and its homologues were also found in sea lamprey and C. elegans.[6] There are two IL-17Rs (IL-17RA and IL-17RD) in the genome of the basal chordate Amphioxus.[7] After two rounds of whole genome duplications, these two IL-17R genes expanded into five early vertebrate IL-17R genes, IL-17RA to IL-17RE. Two (IL-17RA and IL-17RD) are found in most vertebrates, whereas the other three (IL-17RB, IL-17RC and IL-17RE) have undergone some losses in vertebrates during evolution.

Structure

Structure of IL-17 receptors is unique in comparison with all other known receptor families. IL-17RA is by far the largest member of the family and has the longest cytoplasmic tail of the family. This cytoplasmic tail provides docking sites for numerous signaling intermediates. However, conformational changes mediated after ligand binding are essential for association of these signaling molecules as well as the second receptor subunit and enable subsequent signal transduction. IL-17RA/RC receptor complex is composed of both alpha helices and beta sheets and its extracellular part contains two fibronectin domains, which are involved in formation of two ligand binding sites.[8][9]

Intracellular part of IL-17 receptors consists of several structural domains including SEFIR motif, a highly conserved motif within IL-17R family. Although SEFIR motif also serves as signaling molecule in IL-1R or Toll-like receptor families, its signaling features and associated adaptor molecules are quite different in IL-17 receptor family.[10][11] In case of IL-17RA, it has a longer cytoplasmic tail which contains some additional structural domains, such as TILL domain ("TIR-like loop") or inhibitory CBAD domain ("C/EBPβ-activation domain").[11][12]

Expression and regulation

IL-17RA has been observed at high levels in various tissues such as haematopoietic, bone marrow, thymus, and spleen tissue. IL-17RA is also normally found at low levels in colon, small intestine, and lung tissues.[13] IL-17RA is expressed in CD8+ T cells, and upregulated by IL-15 and IL-21. IL-17RA may be internalised after binding IL-17A.[13]

IL-17RB is highly expressed in the kidney, liver and Th2 cells and its overexpression promotes triggering of Th2 immune response.[14][15]

IL-17RC expression is low in haematopoietic tissues and high in non-immune cells of the prostate, liver, kidney, thyroid and joints.[13]

Another family subunit IL-17RE is highly expressed in Th17 cells.[16]

Function

Signaling via IL-17R protects our body against several bacterial and fungal infections caused by invading pathogens, especially against Candida albicans.[17] Binding of proinflammatory cytokin IL-17A to IL-17 receptor causes important conformational changes that enable binding of signaling adaptors, such as Act1 or TRAF proteins. Binding of these signaling adaptors triggers activation of several signaling pathways, including NF-κB, pathways of MAPKs (mitogen-activated protein kinases) or C/EBPs pathway.[18] Activation of these pathways results in expression and production of inflammatory cytokines such as TNFα or IL-1β, chemokines, which drive infiltration of macrophages and antimicrobial products, for example defensins and mucins.[19] All these products contribute to the development of inflammation and elimination of various foreign pathogens. Patients with impaired IL-17R signaling suffer from yeast infections, such as CMC (chronic mucocutaneous candidiasis), or respiratory infections.[20][21]

Apart from production of these inflammatory products de novo, signaling via IL-17R also promotes stabilization of already existent specific mRNA transcripts. This stabilization prolongs the half-life of mRNAs and prevents their quick degradation. Again, these mRNA transcripts predominantly encode proinflammatory cytokines or chemokines.[22]

Pathology

Although IL-17R provides crucial protection against a variety of microbial infections in humans, it must be very strictly regulated. Immoderate and undue activation of IL-17R by IL-17A results in development of several autoimmune diseases, specifically psoriasis or rheumatoid arthritis.[23]

Clinical significance

These days, several monoclonal antibodies neutralizing IL-17A have potential for the treatment of autoimmune diseases in humans, such as plaque psoriasis. Majority of these monoclonal antibodies are humanized IgG1.[24] This therapy may also be soon used for protection against periodontal bone loss as it is currently being tested in mice. IL-17RA has been observed at high levels in people undergoing treatment for cardiac fibroblasts and in certain tissues such as: haematopoietic, bone marrow, thymus, and spleen tissue.[13]

As therapy targets

Approved anti-IL-17(R) drugs include: Brodalumab (Siliq), an antibody targeting IL-17 receptor is approved for the treatment of psoriasis.[25] Ixekizumab and secukinumab approved for plaque psoriasis are antibodies which target IL-17A itself rather than the receptor.[26][27]

See also

References

  1. ↑ PDB: 3JVF​; Ely LK, Fischer S, Garcia KC (December 2009). "Structural basis of receptor sharing by interleukin 17 cytokines". Nature Immunology. 10 (12): 1245–51. doi:10.1038/ni.1813. PMC 2783927. PMID 19838198.
  2. ↑ Yao Z, Spriggs MK, Derry JM, Strockbine L, Park LS, VandenBos T, et al. (November 1997). "Molecular characterization of the human interleukin (IL)-17 receptor". Cytokine. 9 (11): 794–800. doi:10.1006/cyto.1997.0240. PMID 9367539.
  3. ↑ Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, et al. (July 2006). "Cutting edge: interleukin 17 signals through a heteromeric receptor complex". Journal of Immunology. 177 (1): 36–9. doi:10.4049/jimmunol.177.1.36. PMID 16785495.
  4. ↑ Shi Y, Ullrich SJ, Zhang J, Connolly K, Grzegorzewski KJ, Barber MC, et al. (June 2000). "A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity". The Journal of Biological Chemistry. 275 (25): 19167–76. doi:10.1074/jbc.M910228199. PMID 10749887.
  5. ↑ Lee J, Ho WH, Maruoka M, Corpuz RT, Baldwin DT, Foster JS, et al. (January 2001). "IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1". The Journal of Biological Chemistry. 276 (2): 1660–4. doi:10.1074/jbc.M008289200. PMID 11058597.
  6. ↑ Pancer Z, Mayer WE, Klein J, Cooper MD (September 2004). "Prototypic T cell receptor and CD4-like coreceptor are expressed by lymphocytes in the agnathan sea lamprey". Proceedings of the National Academy of Sciences of the United States of America. 101 (36): 13273–8. Bibcode:2004PNAS..10113273P. doi:10.1073/pnas.0405529101. PMC 516559. PMID 15328402.
  7. ↑ Wu B, Jin M, Zhang Y, Wei T, Bai Z (December 2011). "Evolution of the IL17 receptor family in chordates: a new subfamily IL17REL". Immunogenetics. 63 (12): 835–45. doi:10.1007/s00251-011-0554-4. PMID 21732179. S2CID 29049514.
  8. ↑ Gaffen SL (August 2009). "Structure and signalling in the IL-17 receptor family". Nature Reviews. Immunology. 9 (8): 556–67. doi:10.1038/nri2586. PMC 2821718. PMID 19575028.
  9. ↑ Liu S, Song X, Chrunyk BA, Shanker S, Hoth LR, Marr ES, Griffor MC (2013-05-21). "Crystal structures of interleukin 17A and its complex with IL-17 receptor A". Nature Communications. 4 (1): 1888. Bibcode:2013NatCo...4.1888L. doi:10.1038/ncomms2880. PMID 23695682.
  10. ↑ Zhang B, Liu C, Qian W, Han Y, Li X, Deng J (May 2014). "Structure of the unique SEFIR domain from human interleukin 17 receptor A reveals a composite ligand-binding site containing a conserved α-helix for Act1 binding and IL-17 signaling". Acta Crystallographica. Section D, Biological Crystallography. 70 (Pt 5): 1476–83. doi:10.1107/s1399004714005227. PMC 4014126. PMID 24816115.
  11. 1 2 Maitra A, Shen F, Hanel W, Mossman K, Tocker J, Swart D, Gaffen SL (May 2007). "Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression". Proceedings of the National Academy of Sciences of the United States of America. 104 (18): 7506–11. Bibcode:2007PNAS..104.7506M. doi:10.1073/pnas.0611589104. PMC 1863505. PMID 17456598.
  12. ↑ Shen F, Li N, Gade P, Kalvakolanu DV, Weibley T, Doble B, et al. (February 2009). "IL-17 receptor signaling inhibits C/EBPbeta by sequential phosphorylation of the regulatory 2 domain". Science Signaling. 2 (59): ra8. doi:10.1126/scisignal.2000066. PMC 2754870. PMID 19244213.
  13. 1 2 3 4 Ho AW, Gaffen SL (March 2010). "IL-17RC: a partner in IL-17 signaling and beyond". Seminars in Immunopathology. 32 (1): 33–42. doi:10.1007/s00281-009-0185-0. PMC 2837117. PMID 20012905.
  14. ↑ Angkasekwinai P, Park H, Wang YH, Wang YH, Chang SH, Corry DB, et al. (July 2007). "Interleukin 25 promotes the initiation of proallergic type 2 responses". The Journal of Experimental Medicine. 204 (7): 1509–17. doi:10.1084/jem.20061675. PMC 2118650. PMID 17562814.
  15. ↑ Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, et al. (December 2001). "IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo". Immunity. 15 (6): 985–95. doi:10.1016/s1074-7613(01)00243-6. PMID 11754819.
  16. ↑ Chang SH, Reynolds JM, Pappu BP, Chen G, Martinez GJ, Dong C (October 2011). "Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E". Immunity. 35 (4): 611–21. doi:10.1016/j.immuni.2011.09.010. PMC 5800502. PMID 21982598.
  17. ↑ Hernández-Santos N, Gaffen SL (May 2012). "Th17 cells in immunity to Candida albicans". Cell Host & Microbe. 11 (5): 425–35. doi:10.1016/j.chom.2012.04.008. PMC 3358697. PMID 22607796.
  18. ↑ Song X, Qian Y (May 2013). "The activation and regulation of IL-17 receptor mediated signaling". Cytokine. 62 (2): 175–82. doi:10.1016/j.cyto.2013.03.014. PMID 23557798.
  19. ↑ Zenobia C, Hajishengallis G (October 2015). "Basic biology and role of interleukin-17 in immunity and inflammation". Periodontology 2000. 69 (1): 142–59. doi:10.1111/prd.12083. PMC 4530463. PMID 26252407.
  20. ↑ Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, et al. (April 2011). "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity". Science. 332 (6025): 65–8. Bibcode:2011Sci...332...65P. doi:10.1126/science.1200439. PMC 3070042. PMID 21350122.
  21. ↑ Lévy R, Okada S, Béziat V, Moriya K, Liu C, Chai LY, et al. (December 2016). "Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency". Proceedings of the National Academy of Sciences of the United States of America. 113 (51): E8277–E8285. Bibcode:2016PNAS..113E8277L. doi:10.1073/pnas.1618300114. PMC 5187691. PMID 27930337.
  22. ↑ Hartupee J, Liu C, Novotny M, Li X, Hamilton T (September 2007). "IL-17 enhances chemokine gene expression through mRNA stabilization". Journal of Immunology. 179 (6): 4135–41. doi:10.4049/jimmunol.179.6.4135. PMID 17785852.
  23. ↑ Onishi RM, Gaffen SL (March 2010). "Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease". Immunology. 129 (3): 311–21. doi:10.1111/j.1365-2567.2009.03240.x. PMC 2826676. PMID 20409152.
  24. ↑ Jeon C, Sekhon S, Yan D, Afifi L, Nakamura M, Bhutani T (October 2017). "Monoclonal antibodies inhibiting IL-12, -23, and -17 for the treatment of psoriasis". Human Vaccines & Immunotherapeutics. 13 (10): 2247–2259. doi:10.1080/21645515.2017.1356498. PMC 5647990. PMID 28825875.
  25. ↑ Papp K, Leonardi C, Menter A, Thompson EH, Milmont CE, Kricorian G, et al. (December 2014). "Safety and efficacy of brodalumab for psoriasis after 120 weeks of treatment". Journal of the American Academy of Dermatology. 71 (6): 1183–1190.e3. doi:10.1016/j.jaad.2014.08.039. PMID 25313095.
  26. ↑ Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, et al. (March 2012). "Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis". The New England Journal of Medicine. 366 (13): 1190–9. doi:10.1056/nejmoa1109997. PMID 22455413.
  27. ↑ Papp KA, Langley RG, Sigurgeirsson B, Abe M, Baker DR, Konno P, et al. (February 2013). "Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study". The British Journal of Dermatology. 168 (2): 412–21. doi:10.1111/bjd.12110. PMID 23106107. S2CID 10069743.
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