Interleukin-17 receptor

Last updated
Interleukin-17 receptor
Identifiers
SymbolIL17R
Pfam PF08357
InterPro IPR013568
Membranome 8
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
interleukin 17 receptor A
5JVF.pdb.jpg
Crystal structure of a complex of IL-17RA bound to IL-17F in a 1:2 stoichiometry. [1]
Identifiers
Symbol IL17RA
Alt. symbolsIL17R, CDw217
NCBI gene 23765
HGNC 5985
OMIM 605461
RefSeq NM_014339
UniProt Q96F46
Other data
Locus Chr. 22 q11.1
Search for
Structures Swiss-model
Domains InterPro
interleukin 17 receptor B
Identifiers
Symbol IL17RB
Alt. symbolsIL17BR
NCBI gene 55540
HGNC 18015
OMIM 605458
RefSeq NM_172234
UniProt Q9NRM6
Other data
Locus Chr. 3 p21.1
Search for
Structures Swiss-model
Domains InterPro
interleukin 17 receptor C
Identifiers
Symbol IL17RC
Alt. symbolsIL17-RL
NCBI gene 84818
HGNC 18358
OMIM 610925
RefSeq NM_032732
UniProt Q8NAC3
Other data
Locus Chr. 3 p25.3
Search for
Structures Swiss-model
Domains InterPro
Interleukin 17 receptor D
Identifiers
SymbolIL17RD
Alt. symbolsSEF, IL17RLM, FLJ35755, IL-17RD
NCBI gene 54756
HGNC 17616
OMIM 606807
RefSeq NM_017563
UniProt Q8NFM7
Other data
Locus Chr. 3 p21.1
Search for
Structures Swiss-model
Domains InterPro
interleukin 17 receptor E
Identifiers
SymbolIL17RE
Alt. symbolsFLJ23658
NCBI gene 132014
HGNC 18439
RefSeq NM_153480
UniProt Q8NFR9
Other data
Locus Chr. 3 p25.3
Search for
Structures Swiss-model
Domains InterPro
Interleukin 17 receptor E-like
Identifiers
SymbolIL17REL
NCBI gene 400935
HGNC 33808
RefSeq NM_001001694
UniProt Q6ZVW7
Other data
Locus Chr. 22 q13.33
Search for
Structures Swiss-model
Domains InterPro

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.

Contents

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] [ relevant? ]

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

Related Research Articles

<span class="mw-page-title-main">Cytokine</span> Broad and loose category of small proteins important in cell signaling

Cytokines are a broad and loose category of small proteins important in cell signaling. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.

<span class="mw-page-title-main">Interleukin 12</span> Interleukin

Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, helper T cells and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. IL-12 family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.

<span class="mw-page-title-main">Interleukin 26</span>

Interleukin-26 (IL-26) is a protein that in humans is encoded by the IL26 gene.

<span class="mw-page-title-main">Interleukin 25</span> Cytokine that belongs to the IL-17 cytokine family

Interleukin-25 (IL-25) – also known as interleukin-17E (IL-17E) – is a protein that in humans is encoded by the IL25 gene on chromosome 14. IL-25 was discovered in 2001 and is made up of 177 amino acids.

<span class="mw-page-title-main">Interleukin 22</span> Protein, encoded in humans by IL22 gene

Interleukin-22 (IL-22) is protein that in humans is encoded by the IL22 gene.

<span class="mw-page-title-main">Interleukin 20</span> Protein-coding gene in the species Homo sapiens

Interleukin 20 (IL20) is a protein that is in humans encoded by the IL20 gene which is located in close proximity to the IL-10 gene on the 1q32 chromosome. IL-20 is a part of an IL-20 subfamily which is a part of a larger IL-10 family.

<span class="mw-page-title-main">Interleukin 17</span> Group of proteins

Interleukin 17 family is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17A transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17A protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.

T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

<span class="mw-page-title-main">IL17RA</span> Protein-coding gene in the species Homo sapiens

Interleukin 17 receptor A, also known as IL17RA and CDw217, is a human gene.

Interleukin 20 receptors (IL20R) belong to the IL-10 family. IL20R are involved in both pro-inflammatory and anti-inflammatory immune response. There are two types of IL20R: Type I and Type II.

<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

<span class="mw-page-title-main">Interleukin 23</span> Heterodimeric cytokine acting as mediator of inflammation

Interleukin 23 (IL-23) is a heterodimeric cytokine composed of an IL-12B (IL-12p40) subunit and an IL-23A (IL-23p19) subunit. IL-23 is part of the IL-12 family of cytokines. The functional receptor for IL-23 consists of a heterodimer between IL-12Rβ1 and IL-23R.

<span class="mw-page-title-main">IL17RD</span>

Interleukin 17 receptor D is a protein that in humans is encoded by the IL17RD gene.

<span class="mw-page-title-main">Type 3 innate lymphoid cells</span>

Type 3 innate lymphoid cells (ILC3) are immune cells from the lymphoid lineage that are part of the innate immune system. These cells participate in innate mechanisms on mucous membranes, contributing to tissue homeostasis, host-commensal mutualism and pathogen clearance. They are part of a heterogeneous group of innate lymphoid cells, which is traditionally divided into three subsets based on their expression of master transcription factors as well as secreted effector cytokines - ILC1, ILC2 and ILC3.

<span class="mw-page-title-main">CLEC6A</span> Protein-coding gene in humans

Dectin-2 or C-type lectin domain containing 6A is a protein that in humans is encoded by the CLEC6A gene. Dectin-2 is a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. The encoded protein is a type II transmembrane protein with an extracellular carbohydrate recognition domain. It functions as a pattern recognition receptor recognizing α-mannans and as such plays an important role in innate immune response to fungi. Expression is found on macrophages and dendritic cells. It can also be found at low levels in Langerhans cells and peripheral blood monocytes, where expression levels could be increased upon induction of inflammation.

<span class="mw-page-title-main">Interleukin 17F</span>

Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.

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<span class="mw-page-title-main">Act 1 adaptor protein</span> Act 1 adaptor protein

Act 1 adaptor protein is an essential intermediate in the interleukin-17 pathway. The IL-17 protein is a pro-inflammatory cytokine important for tissue inflammation in host defense against infection and in autoimmune disease. It is produced by the CD4 + T cells, in particular the Th17 cells. There are 6 subtypes of IL-17, from IL-17A to IL17-F, these subtypes have nearly identical structures. We know that the cytokines are interacting homotypically, but IL-17A and IL-17F are capable do perform heterotypic interaction too.

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.
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  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. Bibcode:2014AcCrD..70.1476Z. 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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