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

Jerzy Frączek,Tae Whan Kim,Hui Xiao,Jianhong Yao,Qian Wen,Yali Li,Jean-Laurent Casanova,Juliusz Pryjma,Xiaoxia Li

doi:10.1074/jbc.m804779200

Abstract

Two parallel interleukin-1 (IL-1)-mediated signaling pathways have been uncovered for IL-1R-TLR-mediated NFkappaB activation: TAK1-dependent and MEKK3-dependent pathways, respectively. The TAK1-dependent pathway leads to IKKalpha/beta phosphorylation and IKKbeta activation, resulting in classic NFkappaB activation through IkappaBalpha phosphorylation and degradation. The TAK1-independent MEKK3-dependent pathway involves IKKgamma phosphorylation and IKKalpha activation, resulting in NFkappaB activation through dissociation of phosphorylated IkappaBalpha from NFkappaB without IkappaBalpha 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 NFkappaB activation pathway, but mediated IL-1-induced TAK1-independent NFkappaB activation and retained the ability to activate substantial gene expression, indicating a structural role of IRAK4 in mediating this alternative NFkappaB 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 NFkappaB activation.

Highlights

TIR domain, mediating the so-called MyD88-dependent pathway [7]
We report that the kinase activity of IL-1 receptor-associated kinase 4 (IRAK4) is required for IL-1R-TLR-induced TAK1-dependent NF␬B activation pathway, evident by greatly reduced IL-1R-TLR-induced TAK1 phosphorylation and activation, IKK␣/␤ phosphorylation, and I␬B␣ degradation
The fact that the kinase-inactive IRAK4 mutant can still mediate IL-1-induced TAK1-independent NF␬B activation and gene expression indicates a structural role of IRAK4 in mediating this alternative NF␬B activation pathway

Summary

Introduction

TIR domain, mediating the so-called MyD88-dependent pathway [7]. MyD88 recruits serine-threonine kinases IRAK4 (IL-1 receptor-associated kinase 4) and IRAK (8 –12). Inactivation of IRAK4 kinase activity did not affect the levels of TLR/IL-1Rmediated NF␬B activation, a reduction of LPS-, R848-, and IL-1-mediated mRNA stability contributed to the reduced cytokine and chemokine production in bone marrow (BM)derived macrophages from IRAK4 kinase-inactive knock-in mice [18,20] These in vivo studies indicate that IRAK4 kinase activity plays a critical role in TLR-dependent immune responses [21]. By reconstituting IRAK4-deficient mouse embryonic fibroblasts, Lye et al [23] showed that the kinase activity of mouse IRAK4 is required for the optimal transduction of IL-1-induced signals, they found that IRAK4 is capable of mediating some NF␬B activation In support of these previous findings, IL-1-, LPS-, and R848-induced NF␬B activation was not reduced in the BM-derived macrophages from IRAK4 kinase-inactive knock-in mice as compared with that in the wild-type control cells. Deletion analysis of IRAK4 demonstrates the essential structural role of IRAK4 death domain in receptor proximal signaling for mediating IL-1R-TLR-induced NF␬B activation

Methods

Results

Conclusion