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Journal of Virology, January 2008, p. 31-39, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01881-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Cytomegalovirus Specifically Controls the Levels of the Endoplasmic Reticulum Chaperone BiP/GRP78, Which Is Required for Virion Assembly{triangledown}

Nicholas J. Buchkovich,1 Tobi G. Maguire,1 Yongjun Yu,1 Adrienne W. Paton,2 James C. Paton,2 and James C. Alwine1*

Department of Cancer Biology, Abramson Family Cancer Research Institute, Cell and Molecular Biology Graduate Group, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,1 School of Molecular and Biomedical Science, University of Adelaide, S.A. 5005, Australia2

Received 28 August 2007/ Accepted 20 September 2007

The endoplasmic reticulum (ER) chaperone BiP/GRP78 regulates ER function and the unfolded protein response (UPR). Human cytomegalovirus infection of human fibroblasts induces the UPR but modifies it to benefit viral replication. BiP/GRP78 protein levels are tightly regulated during infection, rising after 36 h postinfection (hpi), peaking at 60 hpi, and decreasing thereafter. To determine the effects of this regulation on viral replication, BiP/GRP78 was depleted using the SubAB subtilase cytotoxin, which rapidly and specifically cleaves BiP/GRP78. Toxin treatment of infected cells for 12-h periods beginning at 36, 48, 60, and 84 hpi caused complete loss of BiP but had little effect on viral protein synthesis. However, progeny virion formation was significantly inhibited, suggesting that BiP/GRP78 is important for virion formation. Electron microscopic analysis showed that infected cells were resistant to the toxin and showed none of the cytotoxic effects seen in uninfected cells. However, all viral activity in the cytoplasm ceased, with nucleocapsids remaining in the nucleus or concentrated in the cytoplasmic space just outside of the outer nuclear membrane. These data suggest that one effect of the controlled expression of BiP/GRP78 in infected cells is to aid in cytoplasmic virion assembly and egress.

* Corresponding author. Mailing address: Department of Cancer Biology, 314 Biomedical Research Building, 421 Curie Blvd., School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6142. Phone: (215) 898-3256. Fax: (215) 573-3888. E-mail: alwine{at}mail.med.upenn.edu

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

Journal of Virology, January 2008, p. 31-39, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01881-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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