Abstract
Viral infection triggers activation of transcription factors such as NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and elicit innate antiviral response. Here, we identified MITA as a critical mediator of virus-triggered type I IFN signaling by expression cloning. Overexpression of MITA activated IRF3, whereas knockdown of MITA inhibited virus-triggered activation of IRF3, expression of type I IFNs, and cellular antiviral response. MITA was found to localize to the outer membrane of mitochondria and to be associated with VISA, a mitochondrial protein that acts as an adaptor in virus-triggered signaling. MITA also interacted with IRF3 and recruited the kinase TBK1 to the VISA-associated complex. MITA was phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3. Our results suggest that MITA is a critical mediator of virus-triggered IRF3 activation and IFN expression and further demonstrate the importance of certain mitochondrial proteins in innate antiviral immunity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / immunology
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Adaptor Proteins, Signal Transducing / metabolism*
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Amino Acid Sequence
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Cell Line
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Cloning, Molecular
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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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Interferon Regulatory Factor-3 / metabolism*
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Interferon Type I / immunology
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Interferon Type I / metabolism*
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Intracellular Membranes / metabolism
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Membrane Proteins / chemistry
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mitochondria / metabolism
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Molecular Sequence Data
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism*
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Receptors, Immunologic
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Sendai virus / immunology*
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Sequence Alignment
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Signal Transduction
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Transfection
Substances
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Adaptor Proteins, Signal Transducing
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Interferon Type I
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MAVS protein, human
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Membrane Proteins
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Receptors, Immunologic
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STING1 protein, human
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Protein Serine-Threonine Kinases
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TBK1 protein, human
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RIGI protein, human
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DEAD Box Protein 58
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DEAD-box RNA Helicases