title: Emodin inhibits coxsackievirus B3 replication via multiple signalling cascades leading to suppression of translation.
abstract: CVB3 (coxsackievirus 3) is a primary causal agent of viral myocarditis. Emodin is a natural compound isolated from certain plant roots. In the present study, we found that emodin inhibited CVB3 replication in vitro and in mice, and now we report an unrecognized mechanism by which emodin inhibits CVB3 replication through suppression of viral protein translation via multiple pathways. On one hand, emodin treatment inhibited Akt/mTOR (mammalian target of rapamycin) signalling and activated 4EBP1 (eukaryotic initiation factor 4R-binding protein 1), leading to suppression of translation initiation of ribosomal protein L32 encoded by a 5'-TOP (terminal oligopyrimidine) mRNA. On the other hand, emodin treatment differentially regulated multiple signal cascades, including Akt/mTORC1/p70(S6K) (p70 S6 kinase), ERK1/2 (extracellular-signal-regulated kinase 1/2)/p90(RSK) (p90 ribosomal S6 kinase) and Ca(2+)/calmodulin, leading to activation of eEF2K (eukaryotic elongation factor 2 kinase) and subsequent inactivation of eEF2 (eukaryotic elongation factor 2), resulting in inhibition of CVB3 VP1 (viral protein 1) synthesis. These data imply that eEF2K is a major factor mediating cross-talk of different arms of signalling cascades in this signal network. This notion was verified by either overexpressing eEF2K or treating the cells with siRNAs or eEF2K inhibitor A484954. We showed further that the emodin-induced decrease in p70(S6K) phosphorylation plays a dominant positive role in activation of eEF2K and in turn in conferring the antiviral effect of emodin. This finding was further solidified by expressing constitutively active and dominant-negative Akt. Collectively, our data reveal that emodin inhibits viral replication through impairing translational machinery and suppression of viral translation elongation.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart and Lung Innovation, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6.
authors.forename: Huifang M
authors.initials: HM
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart and Lung Innovation, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6.
authors.forename: Fengping
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart and Lung Innovation, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6.
authors.forename: Ye
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart and Lung Innovation, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6.
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart and Lung Innovation, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6.
authors.forename: Paul
authors.initials: P
authors.lastname: Hanson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart and Lung Innovation, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart and Lung Innovation, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6 decheng.yang@hli.ubc.ca.
authors.forename: Decheng
authors.initials: D
authors.lastname: Yang
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002461:Cell Line, Transformed; D054736:Elongation Factor 2 Kinase / Q000378:metabolism; D004642:Emodin / Q000494:pharmacology*; D029822:Enterovirus B, Human / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019893:Ribosomal Protein S6 Kinases; D054736:Elongation Factor 2 Kinase; D000263:Adenylate Kinase; D004642:Emodin; D002118:Calcium
keywords: 4EBP1; coxsackievirus B3; eEF2K; emodin; mTORC1; p70S6K; translation suppression