Mus musculus Raw sequence reads

Upon RNA virus infection, the signaling adaptor MAVS forms functional prion-like aggregates on mitochondrial outer membrane, which serves as a central hub that links virus recognition to downstream antiviral innate immune responses. Multiple mechanisms regulating MAVS activation have been revealed, however, the checkpoint governing MAVS aggregation remain elusive. Here, we demonstrate that palmitoylation of MAVS at cysteine 79 (C79), mainly catalyzed by palmitoyl S-acyltransferase ZDHHC12, is essential for MAVS aggregation and antiviral innate immunity upon viral infection in macrophages. Notably, systemic lupus erythematosus-associated mutation MAVS C79F is associated with defective palmitoylation, resulting in low type I IFN production. Accordingly, Zdhhc12 deficiency significantly impairs RNA virus-induced type I interferon responses, and the Zdhhc12-deficient mice are highly susceptible to lethal viral infection. These findings uncover a previously unknown mechanism by which the palmitoylation of MAVS is a checkpoint for its aggregation during viral infection to ensure timely activation of antiviral defense.