The SARS-coronavirus membrane protein induces apoptosis via interfering with PDK1-PKB/Akt signalling
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AbstractA number of viral gene products are capable of inducing apoptosis by interfering with various cellular signalling cascades. We previously reported the pro-apoptotic property of the SARS-CoV (severe acute respiratory syndrome coronavirus) M (membrane)protein and a down-regulation of the phosphorylation level of the cell-survival protein PKB (protein kinase B)/Akt in cells expressing M-protein. We also showed that overexpression of PDK1 (3-phosphoinositide-dependent protein kinase 1), the immediate upstream kinase of PKB/Akt, suppressed M-induced apoptosis. This illustrates that M-protein perturbs the PDK1 and PKB/Akt cell survival signalling pathway. In the present study, we demonstrated that the C-terminus of M-protein interacts with the PH (pleckstrin homology) domain of PDK1. This interaction disrupted the association between PDK1 and PKB/Akt, and led to down-regulation of PKB/Akt activity. This subsequently reduced the level of the phosphorylated forkhead transcription factor FKHRL1 and ASK (apoptosis signal-regulating kinase), and led to the activation of caspases 8 and 9. Altogether, our data demonstrate that the SARS-CoV M-protein induces apoptosis through disrupting the interaction of PDK1 with PKB/Akt, and this causes the activation of apoptosis. Our work highlights that the SARS-CoV M protein is highly pro-apoptotic and is capable of simultaneously inducing apoptosis via initiating caspases 8 and 9. Preventing the interaction between M-protein and PDK1 is a plausible therapeutic approach to target the pro-apoptotic property of SARS-CoV.
All Author(s) ListTsoi H, Li L, Chen ZFS, Lau KF, Tsui SKW, Chan HYE
Journal nameBiochemical Journal
Volume Number464
PublisherPortland Press
Pages439 - 447
LanguagesEnglish-United Kingdom
Keywords3-phosphoinositide-dependent protein kinase-1 (PDK1); apoptosis; membrane protein (M-protein); protein kinase B (PKB)/Akt; severe acute respiratory syndrome coronavirus (SARS-CoV)
Web of Science Subject CategoriesBiochemistry & Molecular Biology

Last updated on 2020-30-06 at 03:22