Enterovirus 71 triggering of neuronal apoptosis through activation of Abl-Cdk5 signalling.
The molecular mechanism behind what causes an infection of Enterovirus 71 (EV71) in young children to result in severe neurological diseases is unclear. Herein, we show that Cdk5, a critical signalling effector of various neurotoxic insults in the brain, is activated by EV71 infection of neuronal cells. EV71-induced neuronal apoptosis could be effectively repressed by blocking either Cdk5 kinase activity or its protein expression. Moreover, EV71-induced Cdk5 activation was modulated by c-Abl. The suppression of c-Abl kinase activity by STI571 notably repressed both the Cdk5 activation and neuronal apoptosis in cells infected with EV71. Although EV71 also induces apoptosis in non-neuronal cells, it did not affect Abl and Cdk5 activities in several non-neuronal cell lines. Intriguingly, coxsackievirus A16 (CA16), a genetically closely related serotype to EV71 that usually does not induce severe neurological disorders, could only weakly stimulate Abl, but not Cdk5 kinase activity. Taken together, our data suggest a serotype- and cell type-specific mechanism, by which EV71 induces Abl kinase activity, which in turn triggers Cdk5-signalling for neuronal apoptosis.
Chen
Tsan-Chi
TC
Division of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan.
Lai
Yiu-Kay
YK
Yu
Chun-Keung
CK
Juang
Jyh-Lyh
JL
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004770:Enterovirus / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D016133:Polymerase Chain Reaction; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D016315:Proto-Oncogene Proteins c-abl; D051360:Cyclin-Dependent Kinase 5