Abstract
Detailed understanding of the signaling intermediates that confer the sensing of intracellular viral nucleic acids for induction of type I interferons is critical for strategies to curtail viral mechanisms that impede innate immune defenses. Here we show that the activation of the microtubule-associated guanine nucleotide exchange factor GEF-H1, encoded by Arhgef2, is essential for sensing of foreign RNA by RIG-I-like receptors. Activation of GEF-H1 controls RIG-I-dependent and Mda5-dependent phosphorylation of IRF3 and induction of IFN-β expression in macrophages. Generation of Arhgef2(-/-) mice revealed a pronounced signaling defect that prevented antiviral host responses to encephalomyocarditis virus and influenza A virus. Microtubule networks sequester GEF-H1 that upon activation is released to enable antiviral signaling by intracellular nucleic acid detection pathways.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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COS Cells
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Chlorocebus aethiops
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DEAD Box Protein 58
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DEAD-box RNA Helicases / immunology
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DEAD-box RNA Helicases / metabolism
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Gene Expression / immunology
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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HEK293 Cells
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Humans
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Immunity, Innate / genetics
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Immunity, Innate / immunology*
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Immunoblotting
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Influenza A virus / genetics
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Interferon Regulatory Factor-3 / immunology
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Interferon Regulatory Factor-3 / metabolism
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Interferon-Induced Helicase, IFIH1
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Interferon-beta / genetics
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Interferon-beta / immunology
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Interferon-beta / metabolism
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microscopy, Confocal
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Microtubules / immunology*
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Microtubules / metabolism
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Phosphorylation
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RNA, Viral / immunology*
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Reverse Transcriptase Polymerase Chain Reaction
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Rho Guanine Nucleotide Exchange Factors / genetics
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Rho Guanine Nucleotide Exchange Factors / immunology*
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Rho Guanine Nucleotide Exchange Factors / metabolism
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Signal Transduction / genetics
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Signal Transduction / immunology*
Substances
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Arhgef2 protein, mouse
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Interferon Regulatory Factor-3
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Irf3 protein, mouse
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RNA, Viral
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Rho Guanine Nucleotide Exchange Factors
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Green Fluorescent Proteins
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Interferon-beta
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Ddx58 protein, mouse
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Ifih1 protein, mouse
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DEAD Box Protein 58
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DEAD-box RNA Helicases
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Interferon-Induced Helicase, IFIH1