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The Roles of Two IB Kinase-related Kinases in Lipopolysaccharide and Double Stranded RNA Signaling and Viral Infection

¹ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University and ² Exploratory Research for Advanced Technology Program, Japan Science and Technology Corporation, Osaka 565-0871, Japan
³ Institute of Physical and Chemical Research, Research Center for Allergy and Immunology, Kanagawa 230-0045, Japan

Address correspondence to Shizuo Akira, Dept. of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-8303; Fax: 81-6-6879-8305; email: sakira{at}biken.osaka-u.ac.jp

Viral infection and stimulation with lipopolysaccharide (LPS) or double stranded RNA (dsRNA) induce phosphorylation of interferon (IFN) regulatory factor (IRF)-3 and its translocation to the nucleus, thereby leading to the IFN-ß gene induction. Recently, two IB kinase (IKK)–related kinases, inducible IB kinase (IKK-i) and TANK-binding kinase 1 (TBK1), were suggested to act as IRF-3 kinases and be involved in IFN-ß production in Toll-like receptor (TLR) signaling and viral infection. In this work, we investigated the physiological roles of these kinases by gene targeting. TBK1-deficient embryonic fibroblasts (EFs) showed dramatic decrease in induction of IFN-ß and IFN-inducible genes in response to LPS or dsRNA as well as after viral infection. However, dsRNA-induced expression of these genes was residually detected in TBK1-deficient cells and intact in IKK-i–deficient cells, but completely abolished in IKK-i/TBK1 doubly deficient cells. IRF-3 activation, in response not only to dsRNA but also to viral infection, was impaired in TBK1-deficient cells. Together, these results demonstrate that TBK1 as well as, albeit to a lesser extent, IKK-i play a crucial role in the induction of IFN-ß and IFN-inducible genes in both TLR-stimulated and virus-infected EFs.

Key Words: Toll-like receptor • interferon regulatory factor 3 • NF-B • embryonic fibroblasts • IFN-ß

Abbreviations used in this paper: dsRNA, double stranded RNA; EF, embryonic fibroblast; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal-regulated kinase; IKK, IB kinase; IKK-i, inducible IKK; IRF, IFN regulatory factor; ISRE, IFN-stimulated response element; JNK, c-Jun NH₂-terminal kinase; MAP, mitogen-activated protein; poly(I:C), polyinosine-polycytidylic acid; SeV, Sendai virus; TBK1, TANK-binding kinase 1; TIR, Toll/IL-1 receptor; TLR, Toll-like receptor; TRAF, TNF receptor–associated factor; TRIF, TIR domain-containing adaptor inducing IFN-ß; VSV, vesicular stomatitis virus.

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