Inhibition of glycogen synthase kinase 3β suppresses coxsackievirus-induced cytopathic effect and apoptosis via stabilization of β-catenin

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 3 beta (GSK3 beta). GSK3 beta activity was significantly increased after CVB3 infection and addition of tyrosine kinase inhibitors blocked CVB3-triggered GSK3 beta activation. Inhibition of caspase activity had no inhibitory effect on CVB3-induced CPE; however, blockage of GSK3 beta activation attenuated both CVB3-induced CPE and apoptosis. We further showed that CVB3 infection resulted in reduced beta-catenin protein expression, and GSK3 beta inhibition led to the accumulation and nuclear translocation of beta-catenin. Finally, we found that CVB3-induced CPE and apoptosis were significantly reduced in cells stably overexpressing beta-catenin. Taken together, our results demonstrate that CVB3 infection stimulates GSK3 beta activity via a tyrosine kinase-dependent mechanism, which contributes to CVB3-induced CPE and apoptosis through dysregulation of beta-catenin.