SNX8 modulates the innate immune response to RNA viruses by regulating the aggregation of VISA

The mitochondrial virus-induced signaling adaptor (VISA, also called mitochondrial antiviral signaling, MAVS) protein is a central adaptor in the innate immune response to cytosolic viral RNA. Viral infection causes the aggregation of VISA, which is important for its recruitment of downstream signaling components. How VISA aggregation is regulated remains unknown. Here, we found that sorting nexin 8 (SNX8) is a positive regulator of the RNA virus-triggered induction of downstream effector genes and innate immune response. The brains and lungs of Snx8^-/- mice infected with RNA viruses exhibited lower serum cytokine levels and higher viral titers than those of wild-type mice, resulting in higher lethality. Mechanistically, viral infection induced the translocation of SNX8 from the cytosol to mitochondria and its increased association with VISA, leading to VISA aggregation, its recruitment of downstream signaling components and the induction of downstream antiviral genes. Our findings suggest that SNX8 is a critical component of the RIG-I-like receptor (RLR)-mediated innate immune response by modulating VISA aggregation and activation.