5vi4

Structural highlights

Function

[IL33_MOUSE] Cytokine that binds to and signals through the IL1RL1/ST2 receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells. Involved in the maturation of Th2 cells inducing the secretion of T-helper type 2-associated cytokines. Also involved in activation of mast cells, basophils, eosinophils and natural killer cells. Acts as a chemoattractant for Th2 cells, and may function as an "alarmin", that amplifies immune responses during tissue injury. In quiescent endothelia the uncleaved form is constitutively and abundantly expressed, and acts as a chromatin-associated nuclear factor with transcriptional repressor properties, it may sequester nuclear NF-kappaB/RELA, lowering expression of its targets. This form is rapidely lost upon angiogenic or proinflammatory activation. [IL1AP_MOUSE] Coreceptor for IL1RL2 in the IL-36 signaling system. Coreceptor with IL1R1 in the IL-1 signaling system. Associates with IL1R1 bound to IL1B to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. Recruits TOLLIP to the signaling complex. Does not bind to interleukin-1 alone; binding of IL1RN to IL1R1, prevents its association with IL1R1 to form a signaling complex. The cellular response is modulated through a non-signaling association with the membrane IL1R2 decoy receptor. Secreted forms (isoforms 2 and 3) associate with secreted ligand-bound IL1R2 and increase the affinity of secreted IL1R2 for IL1B; this complex formation may be the dominant mechanism for neutralization of IL1B by secreted/soluble receptors.[UniProtKB:Q9NPH3]^[1] [ILRL1_MOUSE] Receptor for interleukin-33 (IL-33); signaling requires association of the coreceptor IL1RAP (PubMed:18450470, PubMed:17675517). Its stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of MAPK3/ERK1 and/or MAPK1/ERK2, MAPK14, and MAPK8 (By similarity). Possibly involved in helper T-cell function.[UniProtKB:Q01638]^{[2] [3]} Isoform B: Inhibits IL-33 signaling.^[4]

References

1. ↑ Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, Sims JE. Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-36Ra) activity. J Biol Chem. 2011 Dec 9;286(49):42594-602. doi: 10.1074/jbc.M111.267922. Epub, 2011 Sep 29. PMID:21965679 doi:http://dx.doi.org/10.1074/jbc.M111.267922
2. ↑ Chackerian AA, Oldham ER, Murphy EE, Schmitz J, Pflanz S, Kastelein RA. IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex. J Immunol. 2007 Aug 15;179(4):2551-5. PMID:17675517
3. ↑ Palmer G, Lipsky BP, Smithgall MD, Meininger D, Siu S, Talabot-Ayer D, Gabay C, Smith DE. The IL-1 receptor accessory protein (AcP) is required for IL-33 signaling and soluble AcP enhances the ability of soluble ST2 to inhibit IL-33. Cytokine. 2008 Jun;42(3):358-64. doi: 10.1016/j.cyto.2008.03.008. Epub 2008 May, 2. PMID:18450470 doi:http://dx.doi.org/10.1016/j.cyto.2008.03.008
4. ↑ Palmer G, Lipsky BP, Smithgall MD, Meininger D, Siu S, Talabot-Ayer D, Gabay C, Smith DE. The IL-1 receptor accessory protein (AcP) is required for IL-33 signaling and soluble AcP enhances the ability of soluble ST2 to inhibit IL-33. Cytokine. 2008 Jun;42(3):358-64. doi: 10.1016/j.cyto.2008.03.008. Epub 2008 May, 2. PMID:18450470 doi:http://dx.doi.org/10.1016/j.cyto.2008.03.008
5. ↑ Gunther S, Deredge D, Bowers AL, Luchini A, Bonsor DA, Beadenkopf R, Liotta L, Wintrode PL, Sundberg EJ. IL-1 Family Cytokines Use Distinct Molecular Mechanisms to Signal through Their Shared Co-receptor. Immunity. 2017 Sep 19;47(3):510-523.e4. doi: 10.1016/j.immuni.2017.08.004. PMID:28930661 doi:http://dx.doi.org/10.1016/j.immuni.2017.08.004