The hepatitis E virus ORF3 protein stabilizes HIF-1alpha and enhances HIF-1-mediated transcriptional activity through p300/CBP

Cell Microbiol. 2009 Sep;11(9):1409-21. doi: 10.1111/j.1462-5822.2009.01340.x. Epub 2009 Jun 1.


The hepatitis E virus (HEV) causes hepatitis E and is an important human pathogen. We have previously shown that the HEV open reading frame 3 (ORF3) protein promotes survival of the host cell. Here we report finding increased expression of glycolytic pathway enzymes in ORF3-expressing cells. Promoter analysis of these genes revealed the ubiquitous presence of hypoxia inducible factor (HIF) responsive element (HRE). Dominant-negative and siRNA studies showed increased expression of glycolytic pathway genes by the ORF3 to be mediated by the HIF-1 transcription factor. Our results showed that HIF-1alpha, a highly unstable subunit of the HIF-1, was stabilized in ORF3-expressing cells. This was through phosphatidylinositol-3-kinase (PI3K) mediated activation of Akt/protein kinase B. Enhanced binding to the consensus HRE and increased transactivation activity of HIF-1 were also observed in ORF3-expressing cells. The HIF complex recruits the transcriptional adapter/histone acetyltransferase protein p300/CBP to target gene promoters and p300/CBP phosphorylation is required for this interaction. We show that ORF3-mediated extracellularly regulated kinase (Erk) activation was responsible for the observed increase in phosphorylation and transactivation activity of p300/CBP. Our results reveal a two-pronged strategy through which the ORF3 protein might modulate the energy homeostasis in HEV infected cells and thus contribute to pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line
  • E1A-Associated p300 Protein / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Glycolysis
  • Hepatitis E virus / physiology*
  • Host-Pathogen Interactions*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Metabolic Networks and Pathways / genetics
  • Phosphorylation
  • Promoter Regions, Genetic
  • Transcription, Genetic*
  • Viral Proteins / metabolism*


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • ORF3 protein, Hepatitis E virus
  • Viral Proteins
  • E1A-Associated p300 Protein
  • EP300 protein, human