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. 2004 Apr 9;279(15):15652-61.
doi: 10.1074/jbc.M311629200. Epub 2004 Jan 22.

Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways

Ke-Jun Han  1 , Xiaoqin Su, Liang-Guo Xu, Liang-Hua Bin, Jun Zhang, Hong-Bing Shu
Affiliations
Free article

Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways

Ke-Jun Han et al. J Biol Chem. .
Free article

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.

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