Interleukin-1 receptor-associated kinase 4

Definition:

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 to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. 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 NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.

References:

[1]. Sandrine Pacquelet, et al. Cross-talk between IRAK-4 and the NADPH oxidase. Biochem J. 2007 May 1;403(3):451-61. [Content Brief]

[2]. Takahiro Yamamoto, et al. Functional assessment of the mutational effects of human IRAK4 and MyD88 genes. Mol Immunol. 2014 Mar;58(1):66-76. [Content Brief]

[3]. Shyun Li, et al. IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5567-72. [Content Brief]

[4]. Aisling Dunne, et al. IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal). J Biol Chem. 2010 Jun 11;285(24):18276-82. [Content Brief]

[5]. Cyrille Hoarau, et al. TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway. J Immunol. 2007 Oct 1;179(7):4754-65. [Content Brief]

[6]. Alban Ordureau, et al. 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. [Content Brief]

[7]. Jinzhong Qin, et al. 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. [Content Brief]

[8]. Magdalena Koziczak-Holbro, et al. IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and toll-like receptor 7-mediated signaling and gene expression. J Biol Chem. 2007 May 4;282(18):13552-60. [Content Brief]

[9]. Kimberly Burns, et al. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J Exp Med. 2003 Jan 20;197(2):263-8. [Content Brief]

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