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Journal of Virology, June 2001, p. 5491-5497, Vol. 75, No. 12
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.12.5491-5497.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The US3 Protein Kinase Blocks Apoptosis Induced by the d120 Mutant of Herpes Simplex Virus 1 at a Premitochondrial Stage

Joshua Munger, Ana V. Chee, and Bernard Roizman*

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

Received 12 February 2001/Accepted 14 March 2001

Earlier studies have shown that the d120 mutant of herpes simplex virus 1, which lacks both copies of the alpha 4 gene, induces caspase-3-dependent apoptosis in HEp-2 cells. Apoptosis was also induced by the alpha 4 rescuant but was blocked by the complementation of rescuant with a DNA fragment encoding the US3 protein kinase (R. Leopardi and B. Roizman, Proc. Natl. Acad. Sci. USA 93:9583-9587, 1996, and R. Leopardi, C. Van Sant, and B. Roizman, Proc. Natl. Acad. Sci. USA 94:7891-7896, 1997). To investigate its role in the apoptotic cascade, the US3 open reading frame was cloned into a baculovirus (Bac-US3) under the control of the human cytomegalovirus immediate-early promoter. We report the following. (i) Bac-US3 blocks processing of procaspase-3 to active caspase. Procaspase-3 levels remained unaltered if superinfected with Bac-US3 at 3 h after d120 mutant infection, but significant amounts of procaspase-3 remained in cells superinfected with Bac-Us3 at 9 h postinfection with d120 mutant. (ii) The US3 protein kinase blocks the proapoptotic cascade upstream of mitochondrial involvement inasmuch as Bac-US3 blocks release of cytochrome c in cells infected with the d120 mutant. (iii) Concurrent infection of HEp-2 cells with Bac-US3 and the d120 mutant did not alter the pattern of accumulation or processing of ICP0, -22, or -27, and therefore US3 does not appear to block apoptosis by targeting these proteins.

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

Journal of Virology, June 2001, p. 5491-5497, Vol. 75, No. 12
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.12.5491-5497.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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