SARS-CoV-2 membrane glycoprotein M induced caspase-dependent apoptosis in M-expressing African green monkey kidney epithelial Vero E6 cells and in human liver carcinoma HepG2 cells (Ren Y et al. 2021). The expression of viral M in human embryonic kidney 293T (HEK293T) cells inhibited PKB/AKT signaling pathway and reduced the phosphorylated levels of PKB/AKT, FKHRL1 and ASK. The compromised PKB/AKT activity results in apoptosis via caspase activation. Mechanistically, viral M binds to 3-phosphoinositide-dependent protein kinase 1 (PDPK1 or PDK1), inhibiting its phosphorylation activity on the PH domain. This interection prevented AKT binding to PDPK1 thus down-regulating PDPK1-PKB/AKT signaling (Ren Y et al. 2021). Similar findings were reported for the SARS-CoV-1 M protein (Tsoi H et al. 2014), In addition, SARS-CoV-2 N enhanced M-induced apoptosis by strengthening the interaction between M and PDPK1 (Ren Y et al. 2021).