The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands

RIG-I is an essential innate immune receptor for detecting and responding to infection by RNA viruses. RIG-I specifically recognizes the unique molecular features of viral RNA molecules and selectively distinguishes them from closely related RNAs abundant in host cells. The physical basis for this exquisite selectivity is revealed through a series of high-resolution cryo-EM structures of RIG-I in complex with host and viral RNA ligands. These studies demonstrate that RIG-I actively samples double-stranded RNAs in the cytoplasm and distinguishes them by adopting two different types of protein folds. Upon binding viral RNA, RIG-I adopts a high-affinity conformation that is conducive to signaling, while host RNA induces an autoinhibited conformation that stimulates RNA release. By coupling protein folding with RNA binding selectivity, RIG-I distinguishes RNA molecules that differ by as little as one phosphate group, thereby explaining the molecular basis for selective antiviral sensing and the induction of autoimmunity upon RIG-I dysregulation. • Cryo-EM structures of RIG-I complexed with different viral and host RNA ligands • RIG-I adopts two different conformations: one for viral RNA the other for host RNA • RIG-I unfolds its motor domain in order to clamp tightly to the terminus of viral RNA • Bound to host RNA, the motor domain folds and actively facilitates rapid RNA release Wang et al. show that RIG-I uses a domain unfolding event to bind strongly with target viral ligands and an alternative, enzymatically active conformation for sensing and discarding inappropriate host ligands, thereby explaining the molecular basis for selective antiviral sensing and the induction of autoimmunity upon RIG-I dysregulation.