Fig. 1

The apoptosis pathway in SARS-CoV-2 infection. SARS-CoV-2 S protein regulates Bcl-2 and Bax to trigger the intrinsic apoptotic pathway. SARS-CoV-2 M protein stabilizes BOK to trigger intrinsic apoptosis. Additionally, SARS-CoV-2 M interacts with PDK1 and inhibits the activation of PDK1-PKB/AKT signaling to induce caspase-dependent apoptosis. SARS-CoV-2 N improves M-induced apoptosis by interacting with M and PDK1, which can thus strengthen the M-mediated attenuation of PDK1-PKB/AKT interaction. SARS-CoV-2 ORF3a and ORF3b-activated caspase-8 can induce the apoptotic pathway. SARS-CoV-2 ORF6 hinders the nuclear translocation of STAT1. SARS-CoV-2 ORF7b promotes the phosphorylation and nuclear accumulation of IRF3 and STAT1, which activates TNF-α secretion and results in cellular apoptosis through the TNFR1 pathway. SARS-CoV-2 ORF7a recruits Bcl-XL to the ER, activating the cellular ER stress response and enhancing apoptosis. SARS-CoV-2 ORF9b suppresses signaling downstream of MAVS by targeting TOM70. In contrast, SARS-CoV-2 infection activates c-FLIP and NF-κB signaling to hinder apoptosis in infected cells