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

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


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.

Keywords: ARE; AUF1; CaMKII; RNA decay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AU Rich Elements
  • Animals
  • Base Sequence
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cell Line
  • Cells, Cultured
  • Coxsackievirus Infections / genetics*
  • Coxsackievirus Infections / metabolism*
  • Coxsackievirus Infections / pathology
  • DNA-Binding Proteins / metabolism*
  • Enterovirus B, Human / genetics
  • Enterovirus B, Human / physiology*
  • HSP70 Heat-Shock Proteins / genetics*
  • HSP70 Heat-Shock Proteins / metabolism
  • HeLa Cells
  • Heat Shock Transcription Factors
  • Humans
  • Mice
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factors / metabolism*
  • Up-Regulation
  • Virus Replication*


  • DNA-Binding Proteins
  • HSF1 protein, human
  • HSP70 Heat-Shock Proteins
  • Heat Shock Transcription Factors
  • Hsf1 protein, rat
  • Transcription Factors
  • heat-shock protein 70.1
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2