COVID-19 is a current global health threat caused by the novel coronavirus SARS-CoV-2. Emerging evidence indicates that SARS-CoV-2 elicits a dysregulated immune response and a delayed interferons (IFNs) expression in patients, which contribute largely to the viral pathogenesis and development of COVID-19. However, underlying mechanisms remain to be elucidated. Here, we report the activation and repression of innate immune response by SARS-CoV-2. We show that SARS-CoV-2 RNA activates the RIG-I-MAVS-dependent IFN signaling pathway. We further uncover that ORF9b immediately accumulates and antagonizes the antiviral type I IFN response during SARS-CoV-2 infection on primary human pulmonary alveolar epithelial cells. ORF9b targets the NF-κB essential modulator NEMO and interrupts its K63-linked polyubiquitination upon viral stimulation, thereby inhibiting the canonical IKKα/β/γ-NF-κB signaling and subsequent IFN production. Our findings thus unveil the innate immunosuppression by ORF9b, and provide insights into the host-virus interplay during the early stage of SARS-CoV-2 infection.

The monomer-to-filament transition of MAVS is essential for the RIG-I/MDA5mediated antiviral signaling. In quiescent cells, monomeric MAVS is under strict regulation for preventing its spontaneous aggregation, which would result in dysregulated interferon (IFN-a/b) 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 the MAVS transcripts exert a posttranscriptional 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 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.