ATG13 Recruits LC3 to Target H9N2-IAV PB1 for Autophagic-Lysosomal Degradation and Restricts Viral Replication.

Autophagy-related protein 13 (ATG13) is a critical component of the autophagy initiation complex and plays a pivotal role in regulating the initiation of autophagy. However, the precise mechanism by which ATG13 modulates influenza A virus (IAV) replication remains unclear. In this study, we demonstrated that ATG13 specifically interacts with the viral polymerase basic protein 1 (PB1) of H9N2-IAV and facilitates the autophagic degradation of PB1. Mechanistically, ATG13 targeted the C-terminal domain of PB1 and recruits microtubule-associated protein 1 light chain 3 (LC3) to promote the autophagolysosomal degradation of PB1. This process counteracts the PB1-mediated degradation of mitochondrial antiviral signaling protein (MAVS), thereby attenuating the immune evasion capacity of H9N2-IAV and ultimately suppressing viral replication. Collectively, our findings unveil for the first time a molecular mechanism whereby ATG13 negatively regulates IAV replication by mediating the targeted degradation of PB1 via the autophagolysosomal pathway. This study reveals a novel role of the autophagy pathway in host antiviral defense and provides a potential therapeutic target for anti-influenza agents.