title: GEF-H1 controls microtubule-dependent sensing of nucleic acids for antiviral host defenses.
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.
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School.
authors.forename: Hao-Sen
authors.initials: HS
authors.lastname: Chiang
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School.
authors.forename: Joo-Hye
authors.initials: JH
authors.lastname: Song
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center and Center for the Study of Inflammatory Bowel Disease, Harvard Medical School.
authors.forename: Ninghai
authors.initials: N
authors.lastname: Wang
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center and Center for the Study of Inflammatory Bowel Disease, Harvard Medical School.
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.affiliation: Department of Microbiology, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School.
authors.forename: Megha
authors.initials: M
authors.lastname: Basavappa
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Jeffrey
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School.
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Reinecker
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D015151:Immunoblotting; D009980:Influenza A virus / Q000235:genetics; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008870:Microtubules / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D012367:RNA, Viral / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: C577402:Arhgef2 protein, mouse; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D012367:RNA, Viral; D064067:Rho Guanine Nucleotide Exchange Factors; D049452:Green Fluorescent Proteins; D016899:Interferon-beta; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1