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Journal of Virology, April 2006, p. 3752-3764, Vol. 80, No. 8
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.8.3752-3764.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

US3 and US3.5 Protein Kinases of Herpes Simplex Virus 1 Differ with Respect to Their Functions in Blocking Apoptosis and in Virion Maturation and Egress

Alice P. W. Poon, Luca Benetti, and Bernard Roizman*

Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, 910 East 58th Street, Chicago, Illinois 60637

Received 23 November 2005/ Accepted 24 January 2006

Previously, we reported that the US3 protein kinase blocks apoptosis, that it activates protein kinase A (PKA), that activation of PKA blocks apoptosis in cells infected with a US3 deletion mutant, and that an overlapping transcriptional unit encodes a truncated kinase designated US3.5. Here, we report the properties of the kinases based on comparisons of herpes simplex virus and baculoviruses expressing US3 or US3.5 kinase. Specifically, we report the following. (i) Both kinases mediate the phosphorylation of HDAC1, HDAC2, and the PKA regulatory II{alpha} subunit in the absence of other viral proteins. (ii) Both enzymes mediate the phosphorylation of largely identical sets of proteins carrying the phosphorylation consensus site of PKA, but only US3 blocks apoptosis, suggesting that it is US3 and not PKA that is responsible for the phosphorylation of the proteins bearing the shared consensus phosphorylation site and the antiapoptotic activity. (iii) Both kinases cofractionate with mitochondria. Immune depletion of the US3 and US3.5 kinases from the cytoplasm removed the kinases from the supernatant fraction, but not from the mitochondrial fraction, and therefore, if the antiapoptotic activity of the US3 kinase is expressed in mitochondria, the localization signal and the antiapoptotic functions are located on different parts of the protein. (iv) The US3 protein kinase is required for the translocation of virus particles from the nucleus. Although the UL31 protein is phosphorylated in cells infected with the mutant expressing US3.5 kinase, the release of virus particles from nuclei was impeded in some cells, suggesting that the US3 kinase affects the modification of the nuclear membrane more efficiently than the US3.5 kinase.

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

Journal of Virology, April 2006, p. 3752-3764, Vol. 80, No. 8
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.8.3752-3764.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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