Structural highlightsDiseaseIRAK1_HUMAN Systemic lupus erythematosus;Pediatric systemic lupus erythematosus.
FunctionIRAK1_HUMAN Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.[1] [2] [3] [4] [5] [6] [7] [8]
See AlsoReferences
- ↑ Jensen LE, Whitehead AS. IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability. J Biol Chem. 2001 Aug 3;276(31):29037-44. doi: 10.1074/jbc.M103815200. Epub 2001 , Jun 7. PMID:11397809 doi:http://dx.doi.org/10.1074/jbc.M103815200
- ↑ Strelow A, Kollewe C, Wesche H. Characterization of Pellino2, a substrate of IRAK1 and IRAK4. FEBS Lett. 2003 Jul 17;547(1-3):157-61. PMID:12860405
- ↑ Mamidipudi V, Lin C, Seibenhener ML, Wooten MW. Regulation of interleukin receptor-associated kinase (IRAK) phosphorylation and signaling by iota protein kinase C. J Biol Chem. 2004 Feb 6;279(6):4161-5. Epub 2003 Dec 18. PMID:14684752 doi:10.1074/jbc.C300431200
- ↑ Qin J, Jiang Z, Qian Y, Casanova JL, Li X. IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-associated kinase phosphorylation and IL-1 responsiveness. J Biol Chem. 2004 Jun 18;279(25):26748-53. Epub 2004 Apr 14. PMID:15084582 doi:10.1074/jbc.M400785200
- ↑ Huang Y, Li T, Sane DC, Li L. IRAK1 serves as a novel regulator essential for lipopolysaccharide-induced interleukin-10 gene expression. J Biol Chem. 2004 Dec 3;279(49):51697-703. doi: 10.1074/jbc.M410369200. Epub 2004, Oct 1. PMID:15465816 doi:http://dx.doi.org/10.1074/jbc.M410369200
- ↑ Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, Matsuda M, Coban C, Ishii KJ, Kawai T, Takeuchi O, Akira S. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. J Exp Med. 2005 Mar 21;201(6):915-23. doi: 10.1084/jem.20042372. Epub 2005 Mar, 14. PMID:15767370 doi:http://dx.doi.org/10.1084/jem.20042372
- ↑ Ordureau A, Smith H, Windheim M, Peggie M, Carrick E, Morrice N, Cohen P. The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1. Biochem J. 2008 Jan 1;409(1):43-52. PMID:17997719 doi:10.1042/BJ20071365
- ↑ Dunne A, Carpenter S, Brikos C, Gray P, Strelow A, Wesche H, Morrice N, O'Neill LA. IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal). J Biol Chem. 2010 Jun 11;285(24):18276-82. doi: 10.1074/jbc.M109.098137. Epub, 2010 Apr 16. PMID:20400509 doi:10.1074/jbc.M109.098137
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