Swine acute diarrhea syndrome coronavirus nsp5 induces apoptosis by targeting GATA zinc finger domain-containing protein 2A (GATAD2A/p66α)

Swine acute diarrhea syndrome coronavirus (SADS-CoV) causes severe enteric disease in neonatal piglets, resulting in substantial economic losses worldwide. The molecular mechanisms underlying SADS-CoV pathogenesis, particularly how viral proteins modulate host cell death, remain poorly understood. Here, we demonstrated that SADS-CoV infection induces apoptosis in vitro, and that non-structural protein 5 (nsp5) alone is sufficient to trigger apoptotic pathways. We identified GATA zinc finger domain-containing protein 2A (GATAD2A), a core component of the nucleosome remodeling and deacetylation (NuRD) complex, as a novel substrate of SADS-CoV nsp5. Mechanistically, nsp5-mediated cleavage of GATAD2A disrupts the recruitment of chromodomain helicase DNA-binding protein 4 (CHD4), leading to dysregulation of apoptosis-related gene transcription. Mutational analysis revealed that the catalytic residues His41 and Cys144 of nsp5 are essential for its pro-apoptotic activity and oxidative stress induction. Notably, GATAD2A functions as a negative regulator of nsp5-induced apoptosis. Furthermore, SADS-CoV nsp5 cleaves GATAD2A across multiple species, and cleavage at glutamine 531 (Q531) is conserved among nsp5 proteins from SARS-CoV, MERS-CoV, SARS-CoV-2, and PDCoV. Our findings uncover a previously unrecognized mechanism by which coronavirus nsp5 induces apoptosis through targeting GATAD2A. IMPORTANCE Swine acute diarrhea syndrome coronavirus (SADS-CoV) is an emerging coronavirus that poses a significant threat to the global swine industry. The main protease nsp5 represents an attractive antiviral target due to its essential role in viral replication. While previous studies have focused on nsp5’s function in polyprotein processing and immune evasion, its role in regulating host cell death remains largely unexplored. Here, we report the first evidence that SADS-CoV nsp5 induces apoptosis by cleaving GATAD2A, a key component of the NuRD complex. Strikingly, GATAD2A cleavage at Q531 represents a conserved strategy employed by diverse coronaviruses, including SARS-CoV-2, to manipulate host cell fate. This study reveals a novel mechanism of coronavirus pathogenesis and identifies GATAD2A as a potential therapeutic target for broad-spectrum coronavirus intervention.