Protein Synthesis and Endoplasmic Reticulum Stress Can Be Modulated by the Hepatitis C Virus Envelope Protein E2 through the Eukaryotic Initiation Factor 2α Kinase PERK

DOI Web Site 被引用文献2件
  • Nicole Pavio
    Howard Hughes Medical Institute, Department of Molecular Microbiology and Immunology, School of Medicine, University of Southern California, Los Angeles, California 90033
  • Patrick R. Romano
    Department of Biochemistry and Molecular Pharmacology, Jefferson Center for Biomedical Research, Thomas Jefferson University, Doylestown, Pennsylvania 18901
  • Thomas M. Graczyk
    Department of Biochemistry and Molecular Pharmacology, Jefferson Center for Biomedical Research, Thomas Jefferson University, Doylestown, Pennsylvania 18901
  • Stephen M. Feinstone
    Laboratory of Hepatitis Viruses, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892
  • Deborah R. Taylor
    Laboratory of Hepatitis Viruses, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

抄録

<jats:title>ABSTRACT</jats:title> <jats:p>The hepatitis C virus envelope protein, E2, is an endoplasmic reticulum (ER)-bound protein that contains a region of sequence homology with the double-stranded RNA-activated protein kinase PKR and its substrate, the eukaryotic translation initiation factor 2 (eIF2). We previously reported that E2 modulates global translation through inhibition of the interferon-induced antiviral protein PKR through its PKR-eIF2α phosphorylation site homology domain (PePHD). Here we show that the PKR-like ER-resident kinase (PERK) binds to and is also inhibited by E2. At low expression levels, E2 induced ER stress, but at high expression levels, and in vitro, E2 inhibited PERK kinase activity. Mammalian cells that stably express E2 were refractory to the translation-inhibitory effects of ER stress inducers, and E2 relieved general translation inhibition induced by PERK. The PePHD of E2 was required for the rescue of translation that was inhibited by activated PERK, similar to our previous findings with PKR. Here we report the inhibition of a second eIF2α kinase by E2, and these results are consistent with a pseudosubstrate mechanism of inhibition of eIF2α kinases. These findings may also explain how the virus promotes persistent infection by overcoming the cellular ER stress response.</jats:p>

収録刊行物

  • Journal of Virology

    Journal of Virology 77 (6), 3578-3585, 2003-03-15

    American Society for Microbiology

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