title: Coxsackievirus B3 replication is reduced by inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway.
abstract: Coxsackievirus B3 (CVB3) is the most common human pathogen for viral myocarditis. We have previously shown that the signaling protein p21(ras) GTPase-activating protein (RasGAP) is cleaved and that mitogen-activated protein kinases (MAPKs) ERK1/2 are activated in the late phase of CVB3 infection. However, the role of intracellular signaling pathways in CVB3-mediated myocarditis and the relative advantages of such pathways to host or virus remain largely unclear. In this study we extended our prior studies by examining the interaction between CVB3 replication and intracellular signaling pathways in HeLa cells. We observed that CVB3 infection induced a biphasic activation of ERK1/2, early transient activation versus late sustained activation, which were regulated by different mechanisms. Infection by UV-irradiated, inactivated virus capable of receptor binding and endocytosis triggered early ERK1/2 activation, but was insufficient to trigger late ERK1/2 activation. By using a general caspase inhibitor (zVAD.fmk) we further demonstrated that late ERK1/2 activation was not a result of CVB3-mediated caspase cleavage. Treatment of cells with U0126, a selective inhibitor of MAPK kinase (MEK), significantly inhibited CVB3 progeny release and decreased virus protein production. Furthermore, inhibition of ERK1/2 activation circumvented CVB3-induced apoptosis and viral protease-mediated RasGAP cleavage. Taken together, these data suggest that ERK1/2 activation is important for CVB3 replication and contributes to virus-mediated changes in host cells. Our findings demonstrate coxsackievirus takeover of a particular host signaling mechanism and uncover a prospective approach to stymie virus spread and preserve myocardial integrity.
authors.affiliation: Department of Pathology and Laboratory Medicine, McDonald Research Laboratories/The iCAPTURE Center, St. Paul's Hospital/Providence Health Care-University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Honglin
authors.initials: H
authors.lastname: Luo
authors.forename: Bobby
authors.initials: B
authors.lastname: Yanagawa
authors.forename: Jingchun
authors.initials: J
authors.lastname: Zhang
authors.forename: Zongshu
authors.initials: Z
authors.lastname: Luo
authors.forename: Mary
authors.initials: M
authors.lastname: Zhang
authors.forename: Mitra
authors.initials: M
authors.lastname: Esfandiarei
authors.forename: Christopher
authors.initials: C
authors.lastname: Carthy
authors.forename: Janet E
authors.initials: JE
authors.lastname: Wilson
authors.forename: Decheng
authors.initials: D
authors.lastname: Yang
authors.forename: Bruce M
authors.initials: BM
authors.lastname: McManus
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D002070:Butadienes / Q000494:pharmacology; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004770:Enterovirus / Q000254:growth & development / Q000502:physiology* / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011533:Proviruses / Q000254:growth & development; D014466:Ultraviolet Rays; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D002070:Butadienes; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D014764:Viral Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020703:ras GTPase-Activating Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases