Structural Basis for the Prion-Like Mavs Filaments in Antiviral Innate Immunity

Mitochondrial anti-viral signaling (MAVS) protein is a critical adaptor required for innate immune responses against RNA viruses. In virus-infected cells MAVS forms prion-like aggregates to activate antiviral signaling cascades, but the structural mechanism underlying such aggregation is unknown. Here we report cryo-electron microscopic structures of the helical filaments formed by both the N- terminal caspase activation and recruitment domain of MAVS and a truncated MAVS lacking its C-terminal transmembrane domain. Both structures display a left-handed three-stranded helical filament, revealing specific interfaces between individual subunits that are dictated by electrostatic interactions between neighboring strands and conserved hydrophobic interactions within each strand. Point mutations at multiple locations of these two interfaces impaired filament formation and antiviral signaling. Super-resolution imaging of virus-infected cells revealed the spatial features of rod-shaped MAVS clusters on mitochondria. These results elucidate the structural mechanism of MAVS polymerization, and explain how an α-helical domain uses distinct chemical interactions to form self-perpetuating filaments.