title: The SARS-coronavirus membrane protein induces apoptosis via interfering with PDK1-PKB/Akt signalling.
abstract: A 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.
authors.affiliation: *Laboratory of Drosophila Research, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Ho
authors.initials: H
authors.lastname: Tsoi
authors.affiliation: *Laboratory of Drosophila Research, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: *Laboratory of Drosophila Research, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Zhefan S
authors.initials: ZS
authors.lastname: Chen
authors.affiliation: †Biochemistry Programme, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Kwok-Fai
authors.initials: KF
authors.lastname: Lau
authors.affiliation: ║School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Stephen K W
authors.initials: SK
authors.lastname: Tsui
authors.affiliation: *Laboratory of Drosophila Research, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Ho Yin Edwin
authors.initials: HY
authors.lastname: Chan
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D000086862:Coronavirus M Proteins; D057809:HEK293 Cells; D006801:Humans; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D045473:Severe acute respiratory syndrome-related coronavirus / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000086862:Coronavirus M Proteins; C000706237:M protein, SARS-CoV; C000631429:PDK1 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014763:Viral Matrix Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases