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Cell Mol Life Sci. 2016 Mar;73(5):1067-84. doi: 10.1007/s00018-015-2036-6. Epub 2015 Sep 11.

Hsp70-1: upregulation via selective phosphorylation of heat shock factor 1 during coxsackieviral infection and promotion of viral replication via the AU-rich element.

Qiu Y1,2, Ye X1,2, Hanson PJ1,2, Zhang HM1,2, Zong J2, Cho B2, Yang D3,4.

Author information

1
Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.
2
Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
3
Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada. decheng.yang@hli.ubc.ca.
4
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.

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 CaMKII╬│ 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.

KEYWORDS:

ARE; AUF1; CaMKII; RNA decay

PMID:
26361762
DOI:
10.1007/s00018-015-2036-6
[Indexed for MEDLINE]

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