Mechanisms of the TRIF-induced Interferon-stimulated Response Element and NF-κB Activation and Apoptosis Pathways

Ke-Jun Han,Xiaoqin Su,Liang-Guo Xu,Liang-Hua Bin,Jun Zhang,Hong-Bing Shu

doi:10.1074/jbc.m311629200

Abstract

Toll-like receptor-3 is critically involved in host defense against viruses through induction of type I interferons (IFNs). Recent studies suggest that a Toll/interleukin-1 receptor domain-containing adapter protein (TRIF) and two protein kinases (TANK-binding kinase-1 (TBK1) and IkappaB kinase (IKK)-epsilon) are critically involved in Toll-like receptor-3-mediated IFN-beta production through activation of IFN regulatory factor (IRF)-3 and IRF-7. In this study, we demonstrate that TRIF interacts with both IRF-7 and IRF-3. In addition to TBK1 and IKKepsilon, our results indicate that IKKbeta can also phosphorylate IRF-3 and activate the IFN-stimulated response element. TRIF-induced IRF-3 and IRF-7 activation was mediated by TBK1 and its downstream kinases IKKbeta and IKKepsilon. TRIF induced NF-kappaB activation through an IKKbeta- and tumor necrosis factor receptor-associated factor-6-dependent (but not TBK1- and IKKepsilon-dependent) pathway. In addition, TRIF also induced apoptosis through a RIP/FADD/caspase-8-dependent and mitochondrion-independent pathway. Furthermore, our results suggest that the TRIF-induced IFN-stimulated response element and NF-kappaB activation and apoptosis pathways are uncoupled and provide a molecular explanation for the divergent effects induced by the adapter protein TRIF.

Highlights

The Toll/interleukin-1 receptor (TIR)1 family members are evolutionarily conserved proteins that are critically involved in host defense from plants to humans [1,2,3]
Various studies have shown that the TIR domain is required for TIR family membermediated signaling that leads to activation of transcription factors NF-␬B, AP-1, activating transcription factor-2, and interferon regulatory factors (IRFs) and subsequent induction of various chemokines and cytokines that are involved in host defense against the pathogens [1,2,3]
We investigated whether IRF-7 is involved in TRIF signaling

Summary

Introduction

The Toll/interleukin-1 receptor (TIR)1 family members are evolutionarily conserved proteins that are critically involved in host defense from plants to humans [1,2,3]. Both IRF-7⌬N and IRF-3⌬N strongly inhibited TRIF-induced IFN-␤ activation (Fig. 2C). We determined the effects of dominant-negative mutants of TBK1, IKK␤, IKK⑀, and TRAF6 on TRIF-induced ISRE activation. We examined the roles of TRIF, TBK1, IKK␤, IKK⑀, IRF-7, and IRF-3 in Sendai virus-induced ISRE activation.

Results

Conclusion