RIG-I-like receptors (RLRs) are sensors that detect viral RNA in animal cells. RLRs signal to the mitochondrial antiviral signaling (MAVS) adaptor protein to stimulate the formation of a signaling complex that triggers the activation of transcription factors and antiviral gene programs. Gokhale et al. found that an unstructured region within MAVS interacts with the 3′ untranslated regions of cellular RNA, rather than viral RNA, and this was not dependent on RLRs (see the Perspective by Best and Hage). Cellular RNAs influenced the interaction between MAVS and other proteins. Depletion of several proteins that were not previously known to regulate MAVS, but that interacted with MAVS in a cellular RNA–dependent manner, inhibited RLR-dependent antiviral responses. —Sarah H. Ross
