Abstract
The anti-viral type I interferon (IFN) response is initiated by the immediate induction of IFN beta, which is mainly controlled by the IFN-regulatory factor-3 (IRF-3). The signaling pathways mediating viral IRF-3 activation are only poorly defined. We show that the Rho GTPase Rac1 is activated upon virus infection and controls IRF-3 phosphorylation and activity. Inhibition of Rac1 leads to reduced IFN beta promoter activity and to enhanced virus production. As a downstream mediator of Rac signaling towards IRF-3, we have identified the kinase p21-activated kinase (PAK1). Furthermore, both Rac1 and PAK1 regulate the recently described IRF-3 activators, I kappa B kinase- and TANK-binding kinase-1, establishing a first canonical virus-induced IRF-3 activating pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CREB-Binding Protein
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Cell Line
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dimerization
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Dogs
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Enzyme Activation
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Humans
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I-kappa B Kinase
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Influenza A virus / pathogenicity
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Interferon Regulatory Factor-3
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Interferon-beta / genetics
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Nuclear Proteins / metabolism
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Phosphorylation
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Promoter Regions, Genetic / genetics
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Double-Stranded / immunology
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RNA, Double-Stranded / metabolism
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Signal Transduction
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Trans-Activators / metabolism
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Virus Replication
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p21-Activated Kinases
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rac1 GTP-Binding Protein / metabolism*
Substances
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DNA-Binding Proteins
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Nuclear Proteins
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RNA, Double-Stranded
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Trans-Activators
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Transcription Factors
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Interferon-beta
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CREB-Binding Protein
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CREBBP protein, human
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PAK1 protein, human
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Protein Serine-Threonine Kinases
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TBK1 protein, human
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p21-Activated Kinases
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CHUK protein, human
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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rac1 GTP-Binding Protein