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Journal of Virology, March 2003, p. 3578-3585, Vol. 77, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.6.3578-3585.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Nicole Pavio,1,{dagger} Patrick R. Romano,2 Thomas M. Graczyk,2 Stephen M. Feinstone,3 and Deborah R. Taylor3*

Howard Hughes Medical Institute, Department of Molecular Microbiology and Immunology, School of Medicine, University of Southern California, Los Angeles, California 90033,1 Department of Biochemistry and Molecular Pharmacology, Jefferson Center for Biomedical Research, Thomas Jefferson University, Doylestown, Pennsylvania 18901,2 Laboratory of Hepatitis Viruses, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 208923

Received 5 September 2002/ Accepted 13 December 2002

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-eIF2{alpha} 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 eIF2{alpha} kinase by E2, and these results are consistent with a pseudosubstrate mechanism of inhibition of eIF2{alpha} kinases. These findings may also explain how the virus promotes persistent infection by overcoming the cellular ER stress response.

* Corresponding author. Mailing address: 8800 Rockville Pike, HFM-448, Bethesda, MD 20892. Phone: (301) 827-1878. Fax: (301) 496-1810. E-mail: taylord{at}cber.fda.gov.

{dagger} Present address: INSERM U370, Faculte' de Medecine Necker, 75730 Paris Cedex 15, France.

Journal of Virology, March 2003, p. 3578-3585, Vol. 77, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.6.3578-3585.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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