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Journal of Virology, April 1999, p. 3375-3385, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Herpesvirus Ribosome-Associated, RNA-Binding Protein Confers a Growth Advantage upon Mutants Deficient in a GADD34-Related Functiondagger

Matthew Mulvey, Jeremy Poppers, Alison Ladd, and Ian Mohr*

Department of Microbiology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016

Received 5 October 1998/Accepted 4 January 1999

The herpes simplex virus type 1 gamma 34.5 gene product and the cellular GADD34 protein both contain similar domains that can regulate the activity of eukaryotic initiation factor 2 (eIF2), a critical translation initiation factor. Viral mutants that lack the GADD34-related function grow poorly on a variety of malignant human cells, as activation of the cellular PKR kinase leads to the accumulation of inactive, phosphorylated eIF2 at late times postinfection. Termination of translation prior to the completion of the viral reproductive cycle leads to impaired growth. Extragenic suppressors that regain the ability to synthesize proteins efficiently in the absence of the viral GADD34-related function have been isolated. These suppressor alleles are dominant in trans and affect the steady-state accumulation of several viral mRNA species. We demonstrate that deregulated expression of Us11, a virus-encoded RNA-binding, ribosome-associated protein is necessary and sufficient to confer a growth advantage upon viral mutants that lack a GADD34-related function. Ectopic expression of Us11 reduces the accumulation of the activated cellular PKR kinase and allows for sustained protein synthesis. Thus, an RNA-binding, ribosome-associated protein (Us11) and a GADD34-related protein (gamma 34.5) both function in a signal pathway that regulates translation by modulating eIF2 phosphorylation.

* Corresponding author. Mailing address: Department of Microbiology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, 550 First Ave., MSB 214, New York, NY 10016. Phone: (212) 263-0415. Fax: (212) 263-8276. E-mail: mohri01{at}endeavor.med.nyu.edu.

dagger I.M. dedicates this work to the everlasting memories of his father, Donald Mohr, and Yasha Gluzman, a close friend, colleague, and mentor.

Journal of Virology, April 1999, p. 3375-3385, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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