Interleukin-17 receptor explained

interleukin 17 receptor A
Caption:Crystal structure of a complex of IL-17RA bound to IL-17F in a 1:2 stoichiometry.[1]
Hgncid:5985
Symbol:IL17RA
Altsymbols:IL17R, CDw217
Entrezgene:23765
Omim:605461
Refseq:NM_014339
Uniprot:Q96F46
Chromosome:22
Arm:q
Band:11.1
interleukin 17 receptor B
Hgncid:18015
Symbol:IL17RB
Altsymbols:IL17BR
Entrezgene:55540
Omim:605458
Refseq:NM_172234
Uniprot:Q9NRM6
Chromosome:3
Arm:p
Band:21.1
interleukin 17 receptor C
Hgncid:18358
Symbol:IL17RC
Altsymbols:IL17-RL
Entrezgene:84818
Omim:610925
Refseq:NM_032732
Uniprot:Q8NAC3
Chromosome:3
Arm:p
Band:25.3
Interleukin 17 receptor D
Hgncid:17616
Symbol:IL17RD
Altsymbols:SEF, IL17RLM, FLJ35755, IL-17RD
Entrezgene:54756
Omim:606807
Refseq:NM_017563
Uniprot:Q8NFM7
Chromosome:3
Arm:p
Band:21.1
interleukin 17 receptor E
Hgncid:18439
Symbol:IL17RE
Altsymbols:FLJ23658
Entrezgene:132014
Refseq:NM_153480
Uniprot:Q8NFR9
Chromosome:3
Arm:p
Band:25.3
Interleukin 17 receptor E-like
Hgncid:33808
Symbol:IL17REL
Entrezgene:400935
Refseq:NM_001001694
Uniprot:Q6ZVW7
Chromosome:22
Arm:q
Band:13.33

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").[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. 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.

IL-17RB is highly expressed in the kidney, liver and Th2 cells and its overexpression promotes triggering of Th2 immune response.[13] [14]

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

Another family subunit IL-17RE is highly expressed in Th17 cells.[15]

Function

Signaling via IL-17R protects our body against several bacterial and fungal infections caused by invading pathogens, especially against Candida albicans.[16] 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.[17] 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.[18] 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.[19] [20]

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.[21]

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.[22]

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.[23] 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.[24]

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

External links

Notes and References

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  2. Yao Z, Spriggs MK, Derry JM, Strockbine L, Park LS, VandenBos T, Zappone JD, Painter SL, Armitage RJ . 6 . Molecular characterization of the human interleukin (IL)-17 receptor . Cytokine . 9 . 11 . 794–800 . November 1997 . 9367539 . 10.1006/cyto.1997.0240 .
  3. Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, Tocker J, Peschon J . 6 . Cutting edge: interleukin 17 signals through a heteromeric receptor complex . Journal of Immunology . 177 . 1 . 36–9 . July 2006 . 16785495 . 10.4049/jimmunol.177.1.36 . free .
  4. Shi Y, Ullrich SJ, Zhang J, Connolly K, Grzegorzewski KJ, Barber MC, Wang W, Wathen K, Hodge V, Fisher CL, Olsen H, Ruben SM, Knyazev I, Cho YH, Kao V, Wilkinson KA, Carrell JA, Ebner R . 6 . A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity . The Journal of Biological Chemistry . 275 . 25 . 19167–76 . June 2000 . 10749887 . 10.1074/jbc.M910228199 . free .
  5. Lee J, Ho WH, Maruoka M, Corpuz RT, Baldwin DT, Foster JS, Goddard AD, Yansura DG, Vandlen RL, Wood WI, Gurney AL . 6 . IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1 . The Journal of Biological Chemistry . 276 . 2 . 1660–4 . January 2001 . 11058597 . 10.1074/jbc.M008289200 . free .
  6. Pancer Z, Mayer WE, Klein J, Cooper MD . 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 . September 2004 . 15328402 . 516559 . 10.1073/pnas.0405529101 . 2004PNAS..10113273P . free .
  7. Wu B, Jin M, Zhang Y, Wei T, Bai Z . Evolution of the IL17 receptor family in chordates: a new subfamily IL17REL . Immunogenetics . 63 . 12 . 835–45 . December 2011 . 21732179 . 10.1007/s00251-011-0554-4 . 29049514 .
  8. Gaffen SL . Structure and signalling in the IL-17 receptor family . Nature Reviews. Immunology . 9 . 8 . 556–67 . August 2009 . 19575028 . 2821718 . 10.1038/nri2586 .
  9. Liu S, Song X, Chrunyk BA, Shanker S, Hoth LR, Marr ES, Griffor MC . Crystal structures of interleukin 17A and its complex with IL-17 receptor A . Nature Communications . 4 . 1 . 1888 . 2013-05-21 . 23695682 . 10.1038/ncomms2880 . 2013NatCo...4.1888L . free .
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  11. Maitra A, Shen F, Hanel W, Mossman K, Tocker J, Swart D, Gaffen SL . 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 . May 2007 . 17456598 . 1863505 . 10.1073/pnas.0611589104 . 2007PNAS..104.7506M . free .
  12. Shen F, Li N, Gade P, Kalvakolanu DV, Weibley T, Doble B, Woodgett JR, Wood TD, Gaffen SL . 6 . IL-17 receptor signaling inhibits C/EBPbeta by sequential phosphorylation of the regulatory 2 domain . Science Signaling . 2 . 59 . ra8 . February 2009 . 19244213 . 2754870 . 10.1126/scisignal.2000066 .
  13. Angkasekwinai P, Park H, Wang YH, Wang YH, Chang SH, Corry DB, Liu YJ, Zhu Z, Dong C . 6 . Interleukin 25 promotes the initiation of proallergic type 2 responses . The Journal of Experimental Medicine . 204 . 7 . 1509–17 . July 2007 . 17562814 . 2118650 . 10.1084/jem.20061675 .
  14. Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, Menon S, Clifford T, Hunte B, Lesley R, Muchamuel T, Hurst SD, Zurawski G, Leach MW, Gorman DM, Rennick DM . 6 . IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo . Immunity . 15 . 6 . 985–95 . December 2001 . 11754819 . 10.1016/s1074-7613(01)00243-6 . free .
  15. Chang SH, Reynolds JM, Pappu BP, Chen G, Martinez GJ, Dong C . Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E . Immunity . 35 . 4 . 611–21 . October 2011 . 21982598 . 5800502 . 10.1016/j.immuni.2011.09.010 .
  16. Hernández-Santos N, Gaffen SL . Th17 cells in immunity to Candida albicans . Cell Host & Microbe . 11 . 5 . 425–35 . May 2012 . 22607796 . 3358697 . 10.1016/j.chom.2012.04.008 .
  17. Song X, Qian Y . The activation and regulation of IL-17 receptor mediated signaling . Cytokine . 62 . 2 . 175–82 . May 2013 . 23557798 . 10.1016/j.cyto.2013.03.014 .
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  19. Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, Migaud M, Israel L, Chrabieh M, Audry M, Gumbleton M, Toulon A, Bodemer C, El-Baghdadi J, Whitters M, Paradis T, Brooks J, Collins M, Wolfman NM, Al-Muhsen S, Galicchio M, Abel L, Picard C, Casanova JL . 6 . Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity . Science . 332 . 6025 . 65–8 . April 2011 . 21350122 . 3070042 . 10.1126/science.1200439 . 2011Sci...332...65P .
  20. Lévy R, Okada S, Béziat V, Moriya K, Liu C, Chai LY, Migaud M, Hauck F, Al Ali A, Cyrus C, Vatte C, Patiroglu T, Unal E, Ferneiny M, Hyakuna N, Nepesov S, Oleastro M, Ikinciogullari A, Dogu F, Asano T, Ohara O, Yun L, Della Mina E, Bronnimann D, Itan Y, Gothe F, Bustamante J, Boisson-Dupuis S, Tahuil N, Aytekin C, Salhi A, Al Muhsen S, Kobayashi M, Toubiana J, Abel L, Li X, Camcioglu Y, Celmeli F, Klein C, AlKhater SA, Casanova JL, Puel A . 6 . 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 . December 2016 . 27930337 . 5187691 . 10.1073/pnas.1618300114 . 2016PNAS..113E8277L . free .
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  25. Papp K, Leonardi C, Menter A, Thompson EH, Milmont CE, Kricorian G, Nirula A, Klekotka P . 6 . Safety and efficacy of brodalumab for psoriasis after 120 weeks of treatment . Journal of the American Academy of Dermatology . 71 . 6 . 1183–1190.e3 . December 2014 . 25313095 . 10.1016/j.jaad.2014.08.039 .
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