Inhibition of glycogen synthase kinase 3beta suppresses coxsackievirus-induced cytopathic effect and apoptosis via stabilization of beta-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 3beta (GSK3beta). GSK3beta activity was significantly increased after CVB3 infection and addition of tyrosine kinase inhibitors blocked CVB3-triggered GSK3beta activation. Inhibition of caspase activity had no inhibitory effect on CVB3-induced CPE; however, blockage of GSK3beta activation attenuated both CVB3-induced CPE and apoptosis. We further showed that CVB3 infection resulted in reduced beta-catenin protein expression, and GSK3beta 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 GSK3beta activity via a tyrosine kinase-dependent mechanism, which contributes to CVB3-induced CPE and apoptosis through dysregulation of beta-catenin.
Yuan
J
J
Department of Pathology and Laboratory Medicine, The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia - St. Paul's Hospital, Vancouver, British Columbia, Canada.
Zhang
J
J
Wong
B W
BW
Si
X
X
Wong
J
J
Yang
D
D
Luo
H
H
D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D002458:Cell Fractionation; D002460:Cell Line; D002470:Cell Survival; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000378:metabolism*; D029822:Enterovirus B, Human / Q000378:metabolism / Q000502:physiology*; D004769:Enterovirus Infections / Q000201:enzymology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D011991:Receptors, Virus / Q000037:antagonists & inhibitors; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism*; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects; D051176:beta Catenin
C495270:CTNNB1 protein, human; D061945:Caspase Inhibitors; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D011991:Receptors, Virus; D015534:Trans-Activators; D014764:Viral Proteins; D051176:beta Catenin; C105941:coxsackievirus B receptor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3