Molecular Imprinting as a Signal-Activation Mechanism of the Viral RNA Sensor RIG-I

Summary

RIG-I activates interferon signaling pathways by promoting filament formation of the adaptor molecule, MAVS. Assembly of the MAVS filament is mediated by its CARD domain (CARD^MAVS), and requires its interaction with the tandem CARDs of RIG-I (2CARD^RIG-I). However, the precise nature of the interaction between 2CARD^RIG-I and CARD^MAVS, and how this interaction leads to CARD^MAVS filament assembly, has been unclear. Here we report a 3.6 Å electron microscopy structure of the CARD^MAVS filament and a 3.4 Å crystal structure of the 2CARD^RIG-I:CARD^MAVS complex, representing 2CARD^RIG-I "caught in the act" of nucleating the CARD^MAVS filament. These structures, together with functional analyses, show that 2CARD^RIG-I acts as a template for the CARD^MAVS filament assembly, by forming a helical tetrameric structure and recruiting CARD^MAVS along its helical trajectory. Our work thus reveals that signal activation by RIG-I occurs by imprinting its helical assembly architecture on MAVS, a previously uncharacterized mechanism of signal transmission.