Viral SAM-binding proteins nsp14 and NP868R reprogram ATG4A-dependent autophagy from antiviral LC3B activity to GABARAP-mediated mitophagy

Members of the mammalian Atg8-protein family (ATG8), including the MAP1LC3/LC3 and GABARAP subfamilies, play essential roles in selective macroautophagy/autophagy. However, their functional distinctions during viral infection remain poorly understood. Here, we show that S-adenosyl-L-methionine (SAM)-binding viral proteins, such as nsp14 from coronavirus and NP868R from African swine fever virus (ASFV), reprogram autophagy by shifting antiviral LC3B activity toward GABARAP-mediated mitophagy in an ATG4A-dependent manner. Mechanistically, the SAM-binding motif allows these viral proteins to stabilize ATG4A mRNA, thereby increasing ATG4A expression and redirecting autophagic flux from LC3B-mediated virophagy to GABARAP-dependent mitophagy. This shift suppresses innate immune responses by targeting both MAVS-dependent interferon signaling and virophagy, ultimately enhancing viral replication. Collectively, our findings uncover a previously unrecognized immune evasion strategy in which SAM-binding viral proteins rewire autophagy from antiviral to proviral pathways.