Article ; Online: GEF-H1 controls microtubule-dependent sensing of nucleic acids for antiviral host defenses.
2013 Volume 15, Issue 1, Page(s) 63–71
Abstract: ... Activation of GEF-H1 controls RIG-I-dependent and Mda5-dependent phosphorylation of IRF3 and induction of IFN ... guanine nucleotide exchange factor GEF-H1, encoded by Arhgef2, is essential for sensing of foreign RNA by RIG-I-like receptors ... that prevented antiviral host responses to encephalomyocarditis virus and influenza A virus. Microtubule networks ...
| 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. |
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| MeSH term(s) | Animals ; COS Cells ; Chlorocebus aethiops ; DEAD Box Protein 58 ; DEAD-box RNA Helicases/immunology ; DEAD-box RNA Helicases/metabolism ; Gene Expression/immunology ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; HEK293 Cells ; Humans ; Immunity, Innate/genetics ; Immunity, Innate/immunology ; Immunoblotting ; Influenza A virus/genetics ; Interferon Regulatory Factor-3/immunology ; Interferon Regulatory Factor-3/metabolism ; Interferon-Induced Helicase, IFIH1 ; Interferon-beta/genetics ; Interferon-beta/immunology ; Interferon-beta/metabolism ; Macrophages/immunology ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Confocal ; Microtubules/immunology ; Microtubules/metabolism ; Phosphorylation ; RNA, Viral/immunology ; Reverse Transcriptase Polymerase Chain Reaction ; Rho Guanine Nucleotide Exchange Factors/genetics ; Rho Guanine Nucleotide Exchange Factors/immunology ; Rho Guanine Nucleotide Exchange Factors/metabolism ; Signal Transduction/genetics ; Signal Transduction/immunology | ||||||||||
| Chemical Substances | Arhgef2 protein, mouse ; Interferon Regulatory Factor-3 ; Irf3 protein, mouse ; RNA, Viral ; Rho Guanine Nucleotide Exchange Factors ; Green Fluorescent Proteins (147336-22-9) ; Interferon-beta (77238-31-4) ; Ddx58 protein, mouse (EC 3.6.1.-) ; Ifih1 protein, mouse (EC 3.6.1.-) ; DEAD Box Protein 58 (EC 3.6.4.13) ; DEAD-box RNA Helicases (EC 3.6.4.13) ; Interferon-Induced Helicase, IFIH1 (EC 3.6.4.13) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2013-11-24 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural | ||||||||||
| ZDB-ID | 2016987-5 | ||||||||||
| ISSN | 1529-2916 ; 1529-2908 | ||||||||||
| ISSN (online) | 1529-2916 | ||||||||||
| ISSN | 1529-2908 | ||||||||||
| DOI | 10.1038/ni.2766 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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