Control of microtubule-dependent activation of nucleic acid sensors for antiviral host defenses (INM6P.419)

Abstract

Abstract Viral targeting of dynein-based transport mechanisms plays an important role for intracellular movements and replication of viral pathogens. We show that the activation of the microtubule and dynein motor complex-associated guanine nucleotide exchange factor GEF-H1, encoded by Arhgef2, is essential for sensing of foreign RNA by RIG-I-like receptors. GEF-H1-deficient macrophages have a profound defect in the induction of IFN-β following detection of synthetic dsRNAs including HMW and LMW poly(I:C) and 5′ppp-dsRNA. The recognition of viral RNA and synthetic dsRNA in the MAVS pathway required the nucleotide exchange activity of GEF-H1. Furthermore, microtubule networks were required for the activation and interaction of GEF-H1 with TBK1 for IRF3 phosphorylation and subsequent induction of Ifnb1 gene expression. Generation of GEF-H1 deficient mice revealed a pronounced signaling defect that prevented antiviral host responses to encephalomyocarditis virus and influenza A virus. In conclusion, our findings identify GEF-H1 as an antiviral signaling component that directs utilization of TBK1 in the MAVS-dependent nucleic acid detection pathways for the sensing of ssRNA virus infection and induction of IFN-β expression and secretion.