Recombinant Mouse Interleukin-1 receptor-associated kinase 4 (Irak4)

Function

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 (By similarity)

Subcellular Location

Cytoplasm

Subunit

Associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome (PubMed:16951688). Once phosphorylated, IRAK4 dissociates from the receptor complex and then associates with the TNF receptor-associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate complex is required for subsequent NF-kappa-B activation (PubMed:16951688). Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression (By similarity). Interacts with IL1RL1 (By similarity). Interacts (when phosphorylated) with IRAK1 (By similarity). May interact (when phosphorylated) with IRAK3 (By similarity)

• Li S. et al. IRAK4: a novel member of the IRAK family with the properties of an IRAK-kinase. — Proc. Natl. Acad. Sci. U.S.A. (2002)
• Carninci P. et al. The transcriptional landscape of the mammalian genome. — Science (2005)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Suzuki N. et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. — Nature (2002)
• Choi K.C. et al. Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor signaling through direct interaction with the adapter Pellino-1. — Nat. Immunol. (2006)
• Huttlin E.L. et al. A tissue-specific atlas of mouse protein phosphorylation and expression. — Cell (2010)
• Dufner A. et al. B cell antigen receptor-induced activation of an IRAK4-dependent signaling pathway revealed by a MALT1-IRAK4 double knockout mouse model. — Cell Commun. Signal. (2011)
• Lasker M.V. et al. Molecular structure of the IL-1R-associated kinase-4 death domain and its implications for TLR signaling. — J. Immunol. (2005)