The U S 3 Protein Kinase Blocks Apoptosis Induced by the d 120 Mutant of Herpes Simplex Virus 1 at a Premitochondrial Stage

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Abstract
Earlier studies have shown that the d 120 mutant of herpes simplex virus 1, which lacks both copies of the α4 gene, induces caspase-3-dependent apoptosis in HEp-2 cells. Apoptosis was also induced by the α4 rescuant but was blocked by the complementation of rescuant with a DNA fragment encoding the U S 3 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 U S 3 open reading frame was cloned into a baculovirus (Bac-U S 3) under the control of the human cytomegalovirus immediate-early promoter. We report the following. (i) Bac-U S 3 blocks processing of procaspase-3 to active caspase. Procaspase-3 levels remained unaltered if superinfected with Bac-U S 3 at 3 h after d 120 mutant infection, but significant amounts of procaspase-3 remained in cells superinfected with Bac-Us3 at 9 h postinfection with d 120 mutant. (ii) The U S 3 protein kinase blocks the proapoptotic cascade upstream of mitochondrial involvement inasmuch as Bac-U S 3 blocks release of cytochrome c in cells infected with the d 120 mutant. (iii) Concurrent infection of HEp-2 cells with Bac-U S 3 and the d 120 mutant did not alter the pattern of accumulation or processing of ICP0, -22, or -27, and therefore U S 3 does not appear to block apoptosis by targeting these proteins.

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