AMBRA1 promotes dsRNA- and virus-induced apoptosis through interacting with and stabilizing MAVS

Apoptosis is an important cellular response to viral Infection. In this study, we identified activating molecule in Beclin1-regulated Autophagy protein 1 (AMBRA1) as a positive regulator of Apoptosis triggered by double-stranded (ds)RNA. Depletion of AMBRA1 by gene editing significantly reduced dsRNA-induced Apoptosis, which was largely restored by trans-complementation of AMBRA1. Mechanistically, AMBRA1 interacts with mitochondrial antiviral-signaling protein (MAVS), a key mitochondrial adaptor in the Apoptosis pathway induced by dsRNA and viral Infection. Further co-immunoprecipitation analysis demonstrated that the mitochondrial localization of MAVS was essential for their interaction. The impact of AMBRA1 on dsRNA-induced Apoptosis relied on the presence of MAVS and Caspase-8. AMBRA1 was involved in the stabilization of MAVS through preventing its dsRNA-induced proteasomal degradation. Consistently, AMBRA1 upregulated the Apoptosis induced by Semliki Forest virus Infection. Taken together, our work illustrated a role for AMBRA1 in virus-induced Apoptosis through interacting with and stabilizing MAVS.