title: Heat shock protein 70 promotes coxsackievirus B3 translation initiation and elongation via Akt-mTORC1 pathway depending on activation of p70S6K and Cdc2.
abstract: We previously demonstrated that coxsackievirus B3 (CVB3) infection upregulated heat shock protein 70 (Hsp70) and promoted CVB3 multiplication. Here, we report the underlying mechanism by which Hsp70 enhances viral RNA translation. By using an Hsp70-overexpressing cell line infected with CVB3, we found that Hsp70 enhanced CVB3 VP1 translation at two stages. First, Hsp70 induced upregulation of VP1 translation at the initiation stage via upregulation of internal ribosome entry site trans-acting factor lupus autoantigen protein and activation of eIF4E binding protein 1, a cap-dependent translation suppressor. Second, we found that Hsp70 increased CVB3 VP1 translation by enhancing translation elongation. This was mediated by the Akt-mammalian target of rapamycin complex 1 signal cascade, which led to the activation of eukaryotic elongation factor 2 via p70S6K- and cell division cycle protein 2 homolog (Cdc2)-mediated phosphorylation and inactivation of eukaryotic elongation factor 2 kinase. We also determined the position of Cdc2 in this signal pathway, indicating that Cdc2 is regulated by mammalian target of rapamycin complex 1. This signal transduction pathway was validated using a number of specific pharmacological inhibitors, short interfering RNAs (siRNAs) and a dominant negative Akt plasmid. Because Hsp70 is a central component of the cellular network of molecular chaperones enhancing viral replication, these data may provide new strategies to limit this viral infection.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Fengping
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Ye
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
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 Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Hanson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Guangze
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Ronald
authors.initials: R
authors.lastname: Xie
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Lei
authors.initials: L
authors.lastname: Tong
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Decheng
authors.identifier: 0000-0002-3177-0070
authors.initials: D
authors.lastname: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D003384:Coxsackievirus Infections / Q000821:virology; D029822:Enterovirus B, Human / Q000254:growth & development / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D010441:Peptide Chain Elongation, Translational / Q000502:physiology*; D010442:Peptide Chain Initiation, Translational / Q000502:physiology*; D010750:Phosphoproteins / Q000096:biosynthesis; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015678:Viral Structural Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D015852:Eukaryotic Initiation Factor-2; D018840:HSP70 Heat-Shock Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D015678:Viral Structural Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human
keywords: 4EBP1; Akt-mTORC1; CVB3; Cdc2; Hsp70; p70S6K