The Kinase Activity of IL-1 Receptor-associated Kinase 4 Is Required for Interleukin-1 Receptor/Toll-like Receptor-induced TAK1-dependent NFκB Activation

Two parallel interleukin-1 (IL-1)-mediated signaling pathways have been uncovered for IL-1R-TLR-mediated NF kappa B activation: TAK1-dependent and MEKK3-dependent pathways, respectively. The TAK1-dependent pathway leads to IKK alpha/beta phosphorylation and IKK beta activation, resulting in classic NF kappa B activation through I kappa B alpha phosphorylation and degradation. The TAK1-independent MEKK3-dependent pathway involves IKK gamma phosphorylation and IKK beta activation, resulting in NF kappa B activation through dissociation of phosphorylated I kappa B alpha from NF kappa B without I kappa B alpha degradation. IL-1 receptor-associated kinase 4 (IRAK4) belongs to the IRAK family of proteins and plays a critical role in IL-1R/TLR-mediated signaling. IRAK4 kinase-inactive mutant failed to mediate the IL-1R-TLR-induced TAK1-dependent NF kappa B activation pathway, but mediated IL-1-induced TAK1-independent NF kappa B activation and retained the ability to activate substantial gene expression, indicating a structural role of IRAK4 in mediating this alternative NF kappa B activation pathway. Deletion analysis of IRAK4 indicates the essential structural role of the IRAK4 death domain in receptor proximal signaling for mediating IL-1R-TLR-induced NF kappa B activation.