Acetylation-dependent deubiquitinase OTUD3 controls MAVS activation in innate antiviral immunity
Accurate regulation of innate immunity is necessary for the host to efficiently respond to invading pathogen and avoid excessive harmful immune pathology. Here we identified OTUD3 as an acetylation-dependent deubiquitinase that restricts innate antiviral immune signaling. OTUD3 deficiency in mice results in enhanced innate immunity, a diminished viral load, and morbidity. OTUD3 directly hydrolyzes K63-linked poly-ubiquitination of MAVS and thus shuts off innate antiviral immune response. Notably, the catalytic activity of OTUD3 relies on acetylation of its lysine129 residue. In response to virus infection, the acetylated lysine129 is removed by SIRT1, which promptly inactivates OTUD3 and thus allows timely induction of innate antiviral immunity. Importantly, acetyl-OTUD3 levels are inversely correlated with IFN-beta expression in influenza patients. These findings establish OTUD3 as a repressor of MAVS and uncover a previously unknown regulatory mechanism via which the catalytic activity of OTUD3 is tightly controlled to ensure timely activation of antiviral defense.