Abstract
Intracellular detection of RNA virus infection is mediated by the RNA helicase RIG-I, which is recruited to mitochondria by the adaptor protein MAVS and triggers activation of the transcription factors NF-kappaB, IRF3 and IRF7. Here we demonstrate that virus-induced activation of IRF3 and IRF7 depended on the NF-kappaB modulator NEMO, which acted 'upstream' of the kinases TBK1 and IKKepsilon. IRF3 phosphorylation, formation of IRF3 dimers and DNA binding, as well as IRF3-dependent gene expression, were abrogated in NEMO-deficient cells. IRF3 phosphorylation and interferon production were restored by ectopic expression of NEMO. Thus, NEMO, like MAVS, acts as an adaptor protein that allows RIG-I to activate both the NF-kappaB and IRF signaling pathways.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Cell Line
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DEAD Box Protein 58
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DEAD-box RNA Helicases / metabolism
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Humans
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I-kappa B Kinase / genetics
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I-kappa B Kinase / metabolism*
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Interferon Regulatory Factors / metabolism*
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Interferons / biosynthesis
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Interferons / genetics
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Intracellular Signaling Peptides and Proteins / deficiency
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Mice
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Mice, Knockout
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NF-kappa B / metabolism*
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Promoter Regions, Genetic
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism
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RNA Viruses / physiology
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Signal Transduction*
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Virus Replication
Substances
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Adaptor Proteins, Signal Transducing
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IKBKG protein, human
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Interferon Regulatory Factors
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Intracellular Signaling Peptides and Proteins
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NEMO protein, mouse
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NF-kappa B
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TANK protein, human
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Interferons
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Protein Serine-Threonine Kinases
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TBK1 protein, human
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I-kappa B Kinase
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Ddx58 protein, mouse
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DEAD Box Protein 58
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DEAD-box RNA Helicases