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PMID: 15367631 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Activation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity.

Journal of virology ·Vol. 78 ·No. 19 ·2004-10-00 ·Pages 10636-49

tenOever BR, Sharma S, Zou W, Sun Q, Grandvaux N, Julkunen I, Hemmi H, Yamamoto M, Akira S, Yeh WC, Lin R, Hiscott J

Abstract

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 IKKepsilon 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 IKKepsilon 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 IKKepsilon activity. In TBK1-deficient cells, IRF-3 and IRF-7 activation is significantly reduced, although transcriptional upregulation of IKKepsilon following treatment with VSV, double-stranded RNA, or RNP partially compensates for the loss of TBK1. Biochemical analyses with purified TBK1 and IKKepsilon 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 IKKepsilon in epithelial cells. Induction of IKKepsilon potentially functions as a component of the amplification mechanism involved in the establishment of the antiviral state.

MeSH Terms
Cell Line, Tumor Chemokine CCL5/analysis DNA-Binding Proteins/chemistry,immunology,isolation & purification,metabolism Epithelial Cells/metabolism,virology Gene Deletion Humans I-kappa B Kinase Immunity, Innate Interferon Regulatory Factor-3 Interferon Regulatory Factor-7 Interferon Type I/analysis Interferon-alpha Interferons/biosynthesis,immunology Membrane Glycoproteins/immunology,metabolism Phosphorylation Protein Binding Protein Serine-Threonine Kinases/analysis,genetics,isolation & purification,metabolism RNA, Double-Stranded/physiology RNA, Viral/metabolism Receptors, Cell Surface/immunology,metabolism Recombinant Proteins Ribonucleoproteins/metabolism,physiology Signal Transduction Toll-Like Receptors Transcription Factors/chemistry,immunology,isolation & purification,metabolism Vesicular stomatitis Indiana virus/immunology Viral Proteins/metabolism
Chemicals
Chemokine CCL5 DNA-Binding Proteins IRF3 protein, human IRF7 protein, human Interferon Regulatory Factor-3 Interferon Regulatory Factor-7 Interferon Type I Interferon-alpha Membrane Glycoproteins RNA, Double-Stranded RNA, Viral Receptors, Cell Surface Recombinant Proteins Ribonucleoproteins Toll-Like Receptors Transcription Factors Viral Proteins interferon alpha 4A Interferons Protein Serine-Threonine Kinases TBK1 protein, human CHUK protein, human I-kappa B Kinase IKBKB protein, human IKBKE protein, human
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
tenOever Benjamin R
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, 3755 Cote Ste. Catherine, Montreal, Quebec, Canada H3T 1E2.
Sharma Sonia
Zou Wen
Sun Qiang
Grandvaux Nathalie
Julkunen Ilkka
Hemmi Hiroaki
Yamamoto M
Akira Shizuo
Yeh Wen-Chen
Lin Rongtuan
Hiscott John
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.78.19.10636-10649.2004
Published
2004-10-00
Pages
10636-49
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC516426
Subset
IM
External Links
PubMed source DOI: 10.1128/JVI.78.19.10636-10649.2004 PMC Full Text View journal details
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