ATG13 promotes K63-linked polyubiquitination of MAVS via ASB1 to restrict influenza A virus replication.

Autophagy-associated protein 13 (ATG13) plays a pivotal role in regulating the assembly of the autophagy initiation complex. However, the function and mechanism of action of ATG13 during influenza virus infection remain incompletely understood. This study elucidates that ATG13 restricts influenza A virus (IAV) replication while potentiating the activation of the type I interferon (IFN-I) pathway. Mechanistically, coimmunoprecipitation assays revealed that ATG13 interacts with MAVS and recruits the E3 ubiquitin ligase ASB1 to catalyze K63-linked polyubiquitination at the K348 residue, thereby amplifying the downstream antiviral signalling cascade. Furthermore, through dual-luciferase reporter assays and pharmacological inhibition of autophagy, we confirmed that this novel immunomodulatory function of ATG13 is independent of the canonical autophagy pathway. The present study identifies ATG13 as a novel host restriction factor against IAV and reveals a nonautophagic role for ATG13 in antiviral innate immunity.