title: Hsp70-1: upregulation via selective phosphorylation of heat shock factor 1 during coxsackieviral infection and promotion of viral replication via the AU-rich element.
abstract: Coxsackievirus B3 (CVB3) is the primary pathogen of viral myocarditis. Upon infection, CVB3 exploits the host cellular machineries, such as chaperone proteins, to benefit its own infection cycles. Inducible heat shock 70-kDa proteins (Hsp70s) are chaperone proteins induced by various cellular stress conditions. The internal ribosomal entry site (IRES) within Hsp70 mRNA allows Hsp70 to be translated cap-independently during CVB3 infection when global cap-dependent translation is compromised. The Hsp70 protein family contains two major members, Hsp70-1 and Hsp70-2. This study showed that Hsp70-1, but not Hsp70-2, was upregulated during CVB3 infection both in vitro and in vivo. Then a novel mechanism of Hsp70-1 induction was revealed in which CaMKIIγ is activated by CVB3 replication and leads to phosphorylation of heat shock factor 1 (HSF1) specifically at Serine 230, which enhances Hsp70-1 transcription. Meanwhile, phosphorylation of Ser230 induces translocation of HSF1 from the cytoplasm to nucleus, thus blocking the ERK1/2-mediated phosphorylation of HSF1 at Ser307, a negative regulatory process of Hsp70 transcription, further contributing to Hsp70-1 upregulation. Finally, we demonstrated that Hsp70-1 upregulation, in turn, stabilizes CVB3 genome via the AU-rich element (ARE) harbored in the 3' untranslated region of CVB3 genomic RNA.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.|Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
authors.forename: Ye
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.|Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.|Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hanson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.|Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
authors.forename: Huifang Mary
authors.initials: HM
authors.lastname: Zhang
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
authors.forename: Jeff
authors.initials: J
authors.lastname: Zong
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Cho
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada. decheng.yang@hli.ubc.ca.|Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada. decheng.yang@hli.ubc.ca.
authors.forename: Decheng
authors.initials: D
authors.lastname: Yang
mesh_terms: D063307:AU Rich Elements; D000818:Animals; D001483:Base Sequence; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003384:Coxsackievirus Infections / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029822:Enterovirus B, Human / Q000235:genetics / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D014779:Virus Replication
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D014157:Transcription Factors; C081884:heat-shock protein 70.1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: ARE; AUF1; CaMKII; RNA decay