GEF-H1 controls microtubule-dependent sensing of nucleic acids for antiviral host defenses

RIG-I–like receptors are important inducers of innate immunity. Reinecker and colleagues find that activation of the microtubule-associated guanine nucleotide exchange factor GEF-H1 is essential for sensing of foreign RNA by these receptors. 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.