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Journal of Virology, January 2002, p. 743-754, Vol. 76, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.2.743-754.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

US3 Protein Kinase of Herpes Simplex Virus 1 Blocks Caspase 3 Activation Induced by the Products of US1.5 and UL13 Genes and Modulates Expression of Transduced US1.5 Open Reading Frame in a Cell Type-Specific Manner

Ryan Hagglund, Joshua Munger, Alice P. W. Poon, and Bernard Roizman*

The Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, Chicago, Illinois 60637

Received 25 July 2001/ Accepted 11 October 2001

The coding domain of the herpes simplex virus type 1 (HSV-1) {alpha}22 gene encodes two proteins, the 420-amino-acid infected-cell protein 22 (ICP22) and US1.5, a protein colinear with the carboxyl-terminal domain of ICP22. In HSV-1-infected cells, ICP22 and US1.5 are extensively modified by the UL13 and US3 viral protein kinases. In this report, we show that in contrast to other viral proteins defined by their properties as {alpha} proteins, US1.5 becomes detectable and accumulated only at late times after infection. Moreover, significantly more US1.5 protein accumulated in cells infected with a mutant lacking the UL13 gene than in cells infected with wild-type virus. To define the role of viral protein kinases on the accumulation of US1.5 protein, rabbit skin cells or Vero cells were exposed to recombinant baculoviruses that expressed US1.5, UL13, or US3 proteins under a human cytomegalovirus immediate-early promoter. The results were as follows. (i) Accumulation of the US1.5 protein was reduced by concurrent expression of the UL13 protein kinase and augmented by concurrent expression of the US3 protein kinase. The magnitude of the reduction or increase in the accumulation of the US1.5 protein was cell type dependent. The effect of UL13 kinase appears to be specific inasmuch as it did not affect the accumulation of glycoprotein D in cells doubly infected by recombinant baculoviruses expressing these genes. (ii) The reduction in accumulation of the US1.5 protein was partially due to proteasome-dependent degradation. (iii) Both US1.5 and UL13 proteins activated caspase 3, indicative of programmed cell death. (iv) Concurrent expression of the US3 protein kinase blocked activation of caspase 3. The results are concordant with those published elsewhere (J. Munger and B. Roizman, Proc. Natl. Acad. Sci. USA 98:10410–10415, 2001) that the US3 protein kinase can block apoptosis by degradation or posttranslational modification of BAD.

* Corresponding author. Mailing address: The Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, 910 East 58th St., Chicago, IL 60637. Phone: (773) 702-1898. Fax: (773) 702-1631. E-mail: bernard{at}cummings.uchicago.edu.

Journal of Virology, January 2002, p. 743-754, Vol. 76, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.2.743-754.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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