Interleukin-1 (IL-1)-induced TAK1-dependent Versus MEKK3-dependent NFκB Activation Pathways Bifurcate at IL-1 Receptor-associated Kinase Modification

Jianhong Yao,Yi Lu,Zhengfan Jiang,Muhammet Fatih Gulen,Shizuo Akira,Wen Qian,Shintaro Sato,Hui Xiao,Tae Whan Kim,Xiaoxia Li,Joseph DiDonato,Nywana Sizemore,Youcun Qian,Jinzhong Qin,Bing Su

doi:10.1074/jbc.m609039200

Abstract

Interleukin-1 (IL-1) receptor-associated kinase (IRAK) is phosphorylated after it is recruited to the receptor, subsequently ubiquitinated, and eventually degraded upon IL-1 stimulation. Although a point mutation changing lysine 134 to arginine (K134R) in IRAK abolished IL-1-induced IRAK ubiquitination and degradation, mutations of serines and threonines adjacent to lysine 134 to alanines ((S/T)A (131-144)) reduced IL-1-induced IRAK phosphorylation and abolished IRAK ubiquitination. Through the study of these IRAK modification mutants, we uncovered two parallel IL-1-mediated signaling pathways for NFkappaB activation, TAK1-dependent and MEKK3-dependent, respectively. These two pathways bifurcate at the level of IRAK modification. The TAK1-dependent pathway leads to IKKalpha/beta phosphorylation and IKKbeta activation, resulting in classical NFkappaB activation through IkappaBalpha phosphorylation and degradation. The TAK1-independent MEKK3-dependent pathway involves IKKgamma phosphorylation and IKKalpha activation, resulting in NFkappaB activation through IkappaBalpha phosphorylation and subsequent dissociation from NFkappaB but without IkappaBalpha degradation. These results provide significant insight to our further understanding of NFkappaB activation pathways.

Highlights

IL-12-mediated signaling begins when IL-1 binds to the receptor complex, consisting of the IL-1 receptor (IL-1R) and its accessory protein (IL-1RAcp) [1,2,3] (Fig. 1)
IRAK mediates the activation of TAK1 by bringing TRAF6 to form a complex with TAK1-TAB1TAB2-TAB3, which are shown to be preassociated on the membrane
IRAK-deficient cells stably transfected with DD ϩ UD ϩ C1 and K134R were untreated or treated with IL-1 (10 ng/ml)

Summary

Introduction

IL-12-mediated signaling begins when IL-1 binds to the receptor complex, consisting of the IL-1 receptor (IL-1R) and its accessory protein (IL-1RAcp) [1,2,3] (Fig. 1). IL-1-induced I␬B␣ degradation was greatly reduced in IRAKdeficient cells transfected with these IRAK modification mutants (Fig. 3C), implicating a specific role of IRAK modification in the NF␬B activation pathway. Previous studies suggested that MEKK3 plays an important role in IL-1-induced NF␬B activation [28], we recently observed that IL-1 stimulation leads to interaction of IRAK and TRAF6 with MEKK3 (Fig. 4, F and G).

Results

Conclusion