ZNF16 inhibits PEDV replication through autophagy-mediated degradation of S1 protein

Porcine epidemic diarrhea virus (PEDV) is a highly pathogenic virus that causes severe diarrhea and dehydration in piglets, leading to substantial economic losses in swine-producing regions worldwide. In-depth investigation of the interactions between host factors and viral proteins is crucial for the development of PEDV therapeutics or vaccines. This study primarily explores the impact of Zinc finger protein 16 (ZNF16) on PEDV replication. We find that ZNF16 inhibits PEDV proliferation by targeting and degrading the PEDV S1 protein via the autophagy-lysosome pathway. Mechanistically, ZNF16 recruits the E3 ubiquitin ligase STUB1 to facilitate S1 ubiquitination, which is subsequently recognized by the cargo receptor Tollip for translocation to autolysosomes, ultimately leading to viral S1 degradation and inhibition of PEDV replication. Collectively, this work elucidates a novel ZNF16-mediated antiviral mechanism in which the ZNF16-STUB1-Tollip-autolysosome axis promotes viral protein degradation to inhibit PEDV proliferation.