USP13 Cooperates with MARCH8 to Inhibit Antiviral Signaling by Targeting MAVS for Autophagic Degradation in Teleost

Mitochondrial antiviral signaling protein (MAVS), as a central adapter protein in retinoic acid-inducible gene I-like receptor signaling, is indispensable for innate antiviral immunity. Yet, the molecular mechanisms modulating the stability of MAVS are not fully understood in low vertebrates. In this study, we report that the deubiquitinase ubiquitin-specific protease 13 (USP13) acts as a negative regulator of antiviral immunity by targeting MAVS for selective autophagic degradation in teleost fish. USP13 is induced by RNA virus or polyinosinic:polycytidylic acid stimulation and acts as a negative regulator to potentiate viral replication in fish cells. Mechanistically, USP13 functions as a scaffold to enhance the interaction between MAVS and the E3 ubiquitin ligase MARCH8, thus promoting MARCH8 to catalyze MAVS through K27-linked polyubiquitination for selective autophagic degradation. Taken together, to our knowledge, our study demonstrates a novel mechanism by which viruses evade host antiviral immunity via USP13 in fish and provides a new idea for mammalian innate antiviral immunity.