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Interleukin-1 receptor family

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Interleukin-1 receptor
Identifiers
SymbolInterleukin-1 receptor
InterProIPR015621
Membranome13

Members of the very wideinterleukin-1 receptor(IL-1R) family are characterized by extracellularimmunoglobulin-like domains and intracellular Toll/Interleukin-1R (TIR) domain. It is a group of structurally homologous proteins, conserved throughout the species as it was identified from plants to mammals. Proteins of this family play important role in host defence, injury and stress.[1]There are four main groups of TIR domain-containing proteins in animals;Toll-like receptors,Interleukin-1 receptor(IL-1R), cytosolic adaptor proteins (such asMyD88adaptor protein) and insect and nematode Toll. Each of these groups is involved mainly in host defence; Toll receptors are also involved in embryogenesis.[2]

TIR domain

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The TIR domain is about 200amino acidslong and consists of 3 conserved boxes and between these boxes there are regions of variable length. If due to some mutation all of the three boxes are damaged, there is no surface expression of the protein. If only boxes one and two are mutated, there is loss of signalling activity.[2]There are also highly conserved regions between the three boxes as well. When the receptor is activated TIR domain recruits downstream cytoplasmic signalization adaptor proteins (such as Myd88 adaptor protein).[3]

In addition to its traditional role as a scaffolding protein, the TIR domain can also possess intrinsic enzymatic activity to cleave the metaboliteNAD+,as first discovered in the protein SARM1.[4]The ability of TIR domains to consume NAD+is a primordial function of this protein domain, as many TIR domain-containing proteins from bacteria and archaea can degrade NAD+into the productsnicotinamideandADP-ribose(ADPR) (orcyclic-ADPR).[5]

Immunoglobulin-like domain

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Ig-like domain is the part of receptor which is located extracellularly. There are minimal homologies in amino acid sequences of Ig-like domains between proteins of IL-1R family but they all show characteristic Ig-fold and twoβ-sheetsjoined together bydisulfide bondswhich form betweencysteineresidues. There are differences in number of Ig-like domains between members of IL-1R family.[2]

IL-1R signalization

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After ligand binding, the first step of IL-1R family signalling is oligomerization of TIR domains present on receptors (IL-1R,TLR), coreceptors (IL-1R accessory protein,CD14) and adaptor molecules (MyD88). TIR domain present on receptor creates a heterodimer with TIR domain on accessory protein. This high affinity receptor complex recruits downstream signalling molecules. The signal is transduced by cytoplasmatic kinases (such asIRAKs) and by other adaptors, such as tumor necrosis factor 6 (TRAF6). The final step of signalization is phosphorilation of the inhibitory moleculeIkBby IkB kinase complex leading to transcription factorNF-κBreleasing. NF-κB is translocated into nucleus and by binding DNA intermediatesinflammatory,alergic and non-alergic immune response.[6]

Interleukin-1 receptor

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The terminterleukin-1includesIL-1α,IL-1βandInterleukin 1 receptor antagonist(IL-1Ra). IL-1Rs are involved in immune host defence andhematopoiesis.IL-1Rsignalization activates immune response by activation of transcription ofIL-1target genes such asIL-6,IL-8,MCP-1,COX-2,IκBα,IL-1α, IL-1β,MKP-1.Components of signalization pathway of IL-1R which are involved in cellular response to IL-1 also mediate responses to othercytokines(IL-18andIL-33), Toll-like receptors (TLRs), and many forms of cytotoxic stress. IL-1R functions as a bridge between adaptive and innate immunity.

Interleukin 1 receptor, type I

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Type I IL-1R (IL-1RI), also known asCD121a,is receptor forIL-1α,IL-1βandIL-1RA.IL-1RI signalling is involved inthymocyteproliferation,B cellsdevelopment,IL-2and IL-6 production, stress responses, inflammatory responses, sleep regulation and appetite.[2]IL-1RIsignalling plays also important role inTh17development.[7][8]Studies of human autoimmune diseases such assclerosis multiplex,Rheumatoid arthritis,psoriasisor autoimmune inflammatory bowel diseases show that defect in IL-1R1 signalling is responsible for Th17-mediated autoimmune diseases.[9]IL-1Rsignalling is regulated by negative regulators such as inhibitory IL-R1 type II (IL-1RII), soluble IL-1RI and sIL-RII and IL-1Ra.[10]It can be also regulated on the level of downstream signalling molecules by inhibiting recruitment ofIRAKs,or by suppression ofMyD88secretion. IL-1R cooperates with receptor accessory protein and both are expressed onT cells,fibroblastsand endothelial cells.[10]

Interleukin 1 receptor, type II

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IL-1RII is predominantly expressed on lymphoid and myeloid cells includingmonocytes,neutrophils,bone marrowcells,macrophagesandB cells,[11]also onT cellsandepithelial cells.There are three Ig-like domains located extracellulary and highly homological with IL-1RI. Intracellulary there are 24amino acidlong domains which lack the TIR domain thus it is unable to signal.[12]IL-1RII is a surface receptor able to bind IL-1α, IL-1β and IL-1RI. It also forms a soluble form sIL-1RII. It is a decoy receptor – it inhibits activity of its ligands. Expression of IL-1RII is regulated by two different distal 5'UTRs and their associated promoter regions.[13]

IL-1 receptor accessory protein

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IL-1RAcP is a second receptor subunit of IL-1RI. By forming a receptor heterodimer with IL-1RI facilitates signalization due to oligomerization of TIR domains of these proteins.[14]IL-1RAcP does not bind IL-1 but it binds IL-1RI through its Ig-like domains 1 and 2 and is necessary for IL-1R1 signalling. In response to stress oracute phaseinduction, a soluble form of this protein is produced byalternative splicing.[15]

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IL 1 receptor-related protein 2(IL-1R-rp2) consists of three Ig-like extracellular domains, transmembrane domain and cytoplasmic TIR domain. It was detected inlung,epithelium, brain vascular cells and inmonocytes,keratinocytes,fibroblastsandendothelial cells.It activatesNF-κBby binding IL-1ϵ.[16]

References

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  1. ^Bowie A, O'Neill LA (April 2000). "The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products".Journal of Leukocyte Biology.67(4): 508–14.doi:10.1002/jlb.67.4.508.hdl:2262/33703.PMID10770283.
  2. ^abcdBoraschi D, Tagliabue A (2006). "The interleukin-1 receptor family".Vitamins and Hormones.74(4): 229–54.doi:10.1016/s0083-6729(06)74009-2.ISBN9780127098746.PMID17027517.
  3. ^O'Neill LA, Bowie AG (May 2007)."The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling".Nature Reviews. Immunology.7(5): 353–64.doi:10.1038/nri2079.PMID17457343.
  4. ^Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J (March 2017)."+ Cleavage Activity that Promotes Pathological Axonal Degeneration".Neuron.93(6): 1334–1343.e5.doi:10.1016/j.neuron.2017.02.022.PMC6284238.PMID28334607.
  5. ^Essuman K, Summers DW, Sasaki Y, Mao X, Yim AK, DiAntonio A, Milbrandt J (February 2018)."+-Consuming Enzymes".Current Biology.28(3): 421–430.e4.doi:10.1016/j.cub.2017.12.024.PMC5802418.PMID29395922.
  6. ^Martin MU, Wesche H (November 2002)."Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family".Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.1592(3): 265–80.doi:10.1016/S0167-4889(02)00320-8.PMID12421671.
  7. ^Weber A, Wasiliew P, Kracht M (January 2010). "Interleukin-1 (IL-1) pathway".Science Signaling.3(105): cm1.doi:10.1126/scisignal.3105cm1.PMID20086235.
  8. ^Weber A, Wasiliew P, Kracht M (January 2010). "Interleukin-1beta (IL-1beta) processing pathway".Science Signaling.3(105): cm2.doi:10.1126/scisignal.3105cm2.PMID20086236.
  9. ^Dinarello CA (2009). "Immunological and inflammatory functions of the interleukin-1 family".Annual Review of Immunology.27:519–50.doi:10.1146/annurev.immunol.021908.132612.PMID19302047.
  10. ^abSims JE, March CJ, Cosman D, Widmer MB, MacDonald HR, McMahan CJ, Grubin CE, Wignall JM, Jackson JL, Call SM (July 1988). "cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily".Science.241(4865): 585–9.Bibcode:1988Sci...241..585S.doi:10.1126/science.2969618.PMID2969618.
  11. ^McMahan CJ, Slack JL, Mosley B, Cosman D, Lupton SD, Brunton LL, Grubin CE, Wignall JM, Jenkins NA, Brannan CI (October 1991)."A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types".The EMBO Journal.10(10): 2821–32.doi:10.1002/j.1460-2075.1991.tb07831.x.PMC452992.PMID1833184.
  12. ^Colotta F, Re F, Muzio M, Bertini R, Polentarutti N, Sironi M, Giri JG, Dower SK, Sims JE, Mantovani A (July 1993). "Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4".Science.261(5120): 472–5.Bibcode:1993Sci...261..472C.doi:10.1126/science.8332913.PMID8332913.
  13. ^Sims JE, Painter SL, Gow IR (August 1995)."Genomic organization of the type I and type II IL-1 receptors".Cytokine.7(6): 483–90.doi:10.1006/cyto.1995.0066.PMID8580363.
  14. ^O'Neill LA (December 2008). "The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress".Immunological Reviews.226:10–8.doi:10.1111/j.1600-065X.2008.00701.x.PMID19161412.
  15. ^Jensen LE, Muzio M, Mantovani A, Whitehead AS (May 2000)."IL-1 signaling cascade in liver cells and the involvement of a soluble form of the IL-1 receptor accessory protein".Journal of Immunology.164(10): 5277–86.doi:10.4049/jimmunol.164.10.5277.PMID10799889.
  16. ^Lang D, Knop J, Wesche H, Raffetseder U, Kurrle R, Boraschi D, Martin MU (December 1998). "The type II IL-1 receptor interacts with the IL-1 receptor accessory protein: a novel mechanism of regulation of IL-1 responsiveness".Journal of Immunology.161(12): 6871–7.PMID9862719.
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