Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis

Summary The monomer-to-filament transition of MAVS is essential for the RIG-I/MDA5 mediated antiviral signaling. In the quiescent cells, monomeric MAVS is under strict regulation for preventing its spontaneous aggregation, which would result in dysregulated interferon (IFNα/β) production and autoimmune diseases like systemic lupus erythematosus (SLE). However, the detailed mechanism by which MAVS is kept from spontaneous aggregation remains largely unclear. Here, we show that upstream ORFs (uORFs) within the MAVS transcripts exert a post-transcriptional regulation for preventing MAVS spontaneous aggregation and auto-activation. Mechanistically, we demonstrate that uORFs are cis-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 uORFs-deprived transcript spontaneously aggregates, triggering the Nix-mediated mitophagic clearance of damaged mitochondria and aggregated MAVS. Our findings reveal the uORFs-mediated quantity and quality control of MAVS, which prevents aberrant protein aggregation and maintains innate immune homeostasis.