Truncated Forms of Glycoprotein D of Herpes Simplex Virus 1 Capable of Blocking Apoptosis and of Low-Efficiency Entry into Cells Form a Heterodimer Dependent on the Presence of a Cysteine Located in the Shared Transmembrane Domains

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Abstract
Earlier studies have shown that herpes simplex virus 1 (HSV-1) virions of mutant lacking glycoprotein D (gD) and made in either complementing (gD −/+ stocks) or noncomplementing cells (gD −/− stocks) induce apoptosis. Subsequent studies have shown that apoptosis induced by gD −/− mutant virus stocks can be blocked by in trans delivery of viral genes that encode either intact gD or a mixture of two genes encoding the glycoprotein ectodomain plus transmembrane domain (gD-B) and transmembrane domain plus the cytoplasmic carboxyl terminus of the protein (gD-D), respectively. Since the presence of the transmembrane domains was critical for precluding apoptosis in the bipartite system, the question arose whether the two components, gD-B and gD-D, form a heterodimer mediated by an unpaired cysteine located in the transmembrane domain. We report the following. (i) The substitution of the unpaired cysteine with serine in either gD-B or gD-D truncated forms of gD disabled the ability of gD-D and gD-B to block apoptosis. (ii) Immunoprecipitation of gD-D coprecipitated gD-B only from lysates of cells transduced with gD-D and gD-B containing the cysteine in the transmembrane domains. Replacement of cysteine with serine ablated coprecipitation of the components. (ii) The mixture of gD-D and gD-B complemented at a low level gD −/+ virions. We conclude that the gD-B and gD-D can form a heterodimer dependent on the presence of cysteines in the transmembrane domain and the heterodimer can substitute for intact gD but at a much reduced efficiency.

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