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Journal of Virology, April 2007, p. 3377-3390, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02191-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Maintenance of Endoplasmic Reticulum (ER) Homeostasis in Herpes Simplex Virus Type 1-Infected Cells through the Association of a Viral Glycoprotein with PERK, a Cellular ER Stress Sensor{triangledown}

Matthew Mulvey,{dagger} Carolina Arias, and Ian Mohr*

New York University School of Medicine, Department of Microbiology and NYU Cancer Institute, New York, New York 10016

Received 5 October 2006/ Accepted 8 January 2007

In the efforts of viruses to dominate and control critical cellular pathways, viruses generate considerable intracellular stress within their hosts. In particular, the capacity of resident endoplasmic reticulum (ER) chaperones to properly process the acute increase in client protein load is significantly challenged. Such alterations typically induce the unfolded protein response, one component of which acts through IRE1 to restore ER homeostasis by expanding the folding capabilities, whereas the other arm activates the eIF-2{alpha} ({alpha} subunit of eukaryotic initiation factor 2) kinase PERK to transiently arrest production of new polypeptide clientele. Viruses, such as herpes simplex virus type 1 (HSV-1), however, go to great lengths to prevent the inhibition of translation resulting from eIF-2{alpha} phosphorylation. Here, we establish that PERK, but not IRE1, resists activation by acute ER stress in HSV-1-infected cells. This requires the ER luminal domain of PERK, which associates with the viral glycoprotein gB. Strikingly, gB regulates viral protein accumulation in a PERK-dependent manner. This is the first description of a virus-encoded PERK-specific effector and defines a new strategy by which viruses are able to maintain ER homeostasis.

* Corresponding author. Mailing address: NYU School of Medicine, Department of Microbiology, MSB214, 550 First Avenue, New York, NY 10016. Phone: (212) 263-0415. Fax: (212) 263-8276. E-mail: ian.mohr{at}med.nyu.edu.

{triangledown} Published ahead of print on 17 January 2007.

{dagger} Present address: Sequella, Inc., 9610 Medical Center Drive, Rockville, MD 20850.

Journal of Virology, April 2007, p. 3377-3390, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02191-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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