The Mitochondrial Targeting Chaperone 14-3-3ε Regulates a RIG-I Translocon that Mediates Membrane Association and Innate Antiviral Immunity

SummaryRIG-I is a cytosolic pathogen recognition receptor that initiates immune responses against RNA viruses. Upon viral RNA recognition, antiviral signaling requires RIG-I redistribution from the cytosol to membranes where it binds the adaptor protein, MAVS. Here we identify the mitochondrial targeting chaperone protein, 14-3-3ε, as a RIG-I-binding partner and essential component of a translocation complex or “translocon” containing RIG-I, 14-3-3ε, and the TRIM25 ubiquitin ligase. The RIG-I translocon directs RIG-I redistribution from the cytosol to membranes where it mediates MAVS-dependent innate immune signaling during acute RNA virus infection. 14-3-3ε is essential for the stable interaction of RIG-I with TRIM25, which facilitates RIG-I ubiquitination and initiation of innate immunity against hepatitis C virus and other pathogenic RNA viruses. Our results define 14-3-3ε as a key component of a RIG-I translocon required for innate antiviral immunity.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (121 K)Download as PowerPoint slideHighlights► RIG-I undergoes cytosol-to-membrane translocation during acute virus infection ► RNA ligand binding and CARD domains of RIG-I are required for RIG-I translocation ► 14-3-3ε is an essential chaperone protein component of the RIG-I translocon ► RIG-I/14-3-3ε/TRIM25 translocon is essential for antiviral innate immunity