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Journal of Virology, October 2004, p. 10636-10649, Vol. 78, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.19.10636-10649.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Activation of TBK1 and IKK Kinases by Vesicular Stomatitis Virus Infection and the Role of Viral Ribonucleoprotein in the Development of Interferon Antiviral Immunity

Benjamin R. tenOever,^1,2, Sonia Sharma,^1,3, Wen Zou,^1,2 Qiang Sun,^1,2 Nathalie Grandvaux,^1,2 Ilkka Julkunen,⁴ Hiroaki Hemmi,⁵ M. Yamamoto,⁵ Shizuo Akira,⁵ Wen-Chen Yeh,⁶ Rongtuan Lin,^1,2 and John Hiscott^1,2,3*

Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research,¹ Departments of Microbiology and Immunobiology,³ Medicine, McGill University, Montreal, Quebec,² Advanced Medical Discovery Institute, University Health Network and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada,⁶ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Yamada-oka, Suita, Osaka, Japan,⁵ National Public Health Institute, Helsinki, Finland⁴

Received 1 April 2004/ Accepted 17 May 2004

Mounting an immune response to a viral pathogen involves the initial recognition of viral antigens through Toll-like receptor-dependent and -independent pathways and the subsequent triggering of signal transduction cascades. Among the many cellular kinases stimulated in response to virus infection, the noncanonical IKK-related kinases TBK1 and IKK have been shown to phosphorylate and activate interferon regulatory factor 3 (IRF-3) and IRF-7, leading to the production of alpha/beta interferons and the development of a cellular antiviral state. In the present study, we examine the activation of TBK1 and IKK kinases by vesicular stomatitis virus (VSV) infection in human lung epithelial A549 cells. We demonstrate that replication-competent VSV is required to induce activation of the IKK-related kinases and provide evidence that ribonucleoprotein (RNP) complex of VSV generated intracellularly during virus replication can activate TBK1 and IKK activity. In TBK1-deficient cells, IRF-3 and IRF-7 activation is significantly reduced, although transcriptional upregulation of IKK following treatment with VSV, double-stranded RNA, or RNP partially compensates for the loss of TBK1. Biochemical analyses with purified TBK1 and IKK kinases in vitro demonstrate that the two kinases exhibit similar specificities with respect to IRF-3 and IRF-7 substrates and both kinases target serine residues that are important for full transcriptional activation of IRF-3 and IRF-7. These data suggest that intracellular RNP formation contributes to the early recognition of VSV infection, activates the catalytic activity of TBK1, and induces transcriptional upregulation of IKK in epithelial cells. Induction of IKK potentially functions as a component of the amplification mechanism involved in the establishment of the antiviral state.

B.R.T. and S.S. contributed equally to the work.

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