Abstract
The innate immune response to viral infection involves the activation of multiple signaling steps that culminate in the production of type I interferons (IFNs). Mitochondrial antiviral signaling (MAVS), a mitochondrial outer membrane adaptor protein, plays an important role in this process. Here, we report that mitofusin 2 (Mfn2), a mediator of mitochondrial fusion, interacts with MAVS to modulate antiviral immunity. Overexpression of Mfn2 resulted in the inhibition of retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5), two cytosolic sensors of viral RNA, as well as of MAVS-mediated activation of the transcription factors interferon regulatory factor 3 (IRF-3) and nuclear factor kappaB (NF-kappaB). In contrast, loss of endogenous Mfn2 enhanced virus-induced production of IFN-beta and thereby decreased viral replication. Structure-function analysis revealed that Mfn2 interacted with the carboxyl-terminal region of MAVS through a heptad repeat region, providing a structural perspective on the regulation of the mitochondrial antiviral response. Our results suggest that Mfn2 acts as an inhibitor of antiviral signaling, a function that may be distinct from its role in mitochondrial dynamics.
Publication types
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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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Blotting, Western
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Cell Line
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Cells, Cultured
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Chromatography, Gel
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Fibroblasts / cytology
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Fibroblasts / metabolism*
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GTP Phosphohydrolases
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HeLa Cells
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Host-Pathogen Interactions
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Humans
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Immunoprecipitation
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Interferon Regulatory Factor-3 / genetics
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Interferon Regulatory Factor-3 / metabolism
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Measles virus / physiology
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Mitochondria / metabolism*
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Mitochondria / virology
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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Models, Biological
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA Interference
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / metabolism
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Transfection
Substances
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Adaptor Proteins, Signal Transducing
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Interferon Regulatory Factor-3
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MAVS protein, human
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Membrane Proteins
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Mitochondrial Proteins
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NF-kappa B
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TNF Receptor-Associated Factor 6
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Protein Serine-Threonine Kinases
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TBK1 protein, human
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GTP Phosphohydrolases
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MFN2 protein, human