摘要：SummaryThe monomer-to-filament transition of MAVS is essential for the RIG-I/MDA5-mediated antiviral signaling. In quiescent cells, monomeric MAVS is under strict regulation for preventing its spontaneous aggregation, which would result in dysregulated interferon (IFN-α/β) production and autoimmune diseases like systemic lupus erythematosus. However, the detailed mechanism by which MAVS is kept from spontaneous aggregation remains largely unclear. Here, we show that upstream open reading frames (uORFs) within theMAVStranscripts exert a post-transcriptional regulation for preventing MAVS spontaneous aggregation and auto-activation. Mechanistically, we demonstrate that uORFs arecis-acting elements initiating leaky ribosome scanning of the downstream ORF codons, thereby repressing the full-length MAVS translation. We further uncover that endogenous MAVS generated from the uORF-deprived transcript spontaneously aggregates, triggering the Nix-mediated mitophagic clearance of damaged mitochondria and aggregated MAVS. Our findings reveal the uORF-mediated quantity and quality control of MAVS, which prevents aberrant protein aggregation and maintains innate immune homeostasis.Graphical AbstractDisplay OmittedHighlights•uORFs are safety checks preventing MAVS spontaneous aggregation and auto-activation•uORFs exert the quantity and quality control of MAVS•Spontaneously aggregated MAVS induces an antiviral state in quiescent cells•Nix mediates the cargo selection and mitophagic clearance of MAVS aggregatesBiological Sciences; Cell Biology; Immunology; Molecular Biology
