Abstract
Coxsackievirus B3 (CVB3), a common human pathogen for viral myocarditis, induces a direct cytopathic effect (CPE) and apoptosis on infected cells. To elucidate the mechanisms that contribute to these processes, we studied the role of glycogen synthase kinase 3β (GSK3β). GSK3β activity was significantly increased after CVB3 infection and addition of tyrosine kinase inhibitors blocked CVB3-triggered GSK3β activation. Inhibition of caspase activity had no inhibitory effect on CVB3-induced CPE; however, blockage of GSK3β activation attenuated both CVB3-induced CPE and apoptosis. We further showed that CVB3 infection resulted in reduced β-catenin protein expression, and GSK3β inhibition led to the accumulation and nuclear translocation of β-catenin. Finally, we found that CVB3-induced CPE and apoptosis were significantly reduced in cells stably overexpressing β-catenin. Taken together, our results demonstrate that CVB3 infection stimulates GSK3β activity via a tyrosine kinase-dependent mechanism, which contributes to CVB3-induced CPE and apoptosis through dysregulation of β-catenin.
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Abbreviations
- CVB3:
-
coxsackievirus B3
- GSK3β:
-
glycogen synthase kinase 3β
- CPE:
-
cytopathic effect
- PI3K:
-
phosphatidylinositol 3 kinase
- PKB:
-
protein kinase B
- TCF/TEF:
-
T-cell factor/lymphocyte enhancer factor
- LiCl:
-
lithium chloride
- MOI:
-
multiplicity of infection
- PFU:
-
plaque-forming unit
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Acknowledgements
We thank Drs. Bert Vogelstein and Kenneth W Kinzler (The Johns Hopkins University, Baltimore) for providing the pCIneo-β-catenin plasmid. This work was funded by grant from the Hospital for Sick Kids Foundation/Canadian Institutes of Health Research (CIHR) (HL). JY and BWW are the recipients of a Doctoral Traineeship from the Heart and Stroke Foundation of Canada. BWW is the recipient of a CIHR Michael Smith Doctoral Research Award. XS is supported by a CIHR IMPACT Post-Doctoral Fellowship. HL is a New Investigator of the CIHR/St. Paul's Hospital Foundation Award and a Scholar of the Michael Smith Foundation for Health Research.
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Yuan, J., Zhang, J., Wong, B. et al. Inhibition of glycogen synthase kinase 3β suppresses coxsackievirus-induced cytopathic effect and apoptosis via stabilization of β-catenin. Cell Death Differ 12, 1097–1106 (2005). https://doi.org/10.1038/sj.cdd.4401652
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DOI: https://doi.org/10.1038/sj.cdd.4401652
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