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. 1988 Mar;62(3):732–743. doi: 10.1128/jvi.62.3.732-743.1988

Physical and functional domains of the herpes simplex virus transcriptional regulatory protein ICP4.

N A DeLuca 1, P A Schaffer 1
PMCID: PMC253626  PMID: 2828668

Abstract

A characteristic common to DNA animal viruses is the expression early in infection of viral proteins that act in trans to regulate subsequent RNA polymerase II-dependent transcription of the remainder of the viral genome. The predominant transcriptional regulatory protein specified by herpes simplex virus type 1 is the immediate-early protein ICP4. ICP4 is a complex multifunctional protein required for the activation of many herpes simplex virus type 1 transcriptional units and for repression of its own transcription. In the present study we have introduced nonsense and deletion mutations into both genome copies of the ICP4 gene such that the resulting mutants express only defined subsets of the primary ICP4 amino acid sequence. The partial peptides retain activities and physical properties of the intact ICP4 molecule, permitting one to attribute individual activities and properties to defined amino acid sequences.

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Selected References

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  1. Alwine J. C., Steinhart W. L., Hill C. W. Transcription of herpes simplex type 1 DNA in nuclei isolated from infected HEp-2 and KB cells. Virology. 1974 Jul;60(1):302–307. doi: 10.1016/0042-6822(74)90390-0. [DOI] [PubMed] [Google Scholar]
  2. Batterson W., Roizman B. Characterization of the herpes simplex virion-associated factor responsible for the induction of alpha genes. J Virol. 1983 May;46(2):371–377. doi: 10.1128/jvi.46.2.371-377.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beard P., Faber S., Wilcox K. W., Pizer L. I. Herpes simplex virus immediate early infected-cell polypeptide 4 binds to DNA and promotes transcription. Proc Natl Acad Sci U S A. 1986 Jun;83(11):4016–4020. doi: 10.1073/pnas.83.11.4016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Campbell M. E., Palfreyman J. W., Preston C. M. Identification of herpes simplex virus DNA sequences which encode a trans-acting polypeptide responsible for stimulation of immediate early transcription. J Mol Biol. 1984 Nov 25;180(1):1–19. doi: 10.1016/0022-2836(84)90427-3. [DOI] [PubMed] [Google Scholar]
  5. Clements J. B., Watson R. J., Wilkie N. M. Temporal regulation of herpes simplex virus type 1 transcription: location of transcripts on the viral genome. Cell. 1977 Sep;12(1):275–285. doi: 10.1016/0092-8674(77)90205-7. [DOI] [PubMed] [Google Scholar]
  6. Coen D. M., Weinheimer S. P., McKnight S. L. A genetic approach to promoter recognition during trans induction of viral gene expression. Science. 1986 Oct 3;234(4772):53–59. doi: 10.1126/science.3018926. [DOI] [PubMed] [Google Scholar]
  7. Cordingley M. G., Campbell M. E., Preston C. M. Functional analysis of a herpes simplex virus type 1 promoter: identification of far-upstream regulatory sequences. Nucleic Acids Res. 1983 Apr 25;11(8):2347–2365. doi: 10.1093/nar/11.8.2347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Costanzo F., Campadelli-Fiume G., Foa-Tomasi L., Cassai E. Evidence that herpes simplex virus DNA is transcribed by cellular RNA polymerase B. J Virol. 1977 Mar;21(3):996–1001. doi: 10.1128/jvi.21.3.996-1001.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Courtney R. J., Benyesh-Melnick M. Isolation and characterization of a large molecular-weight polypeptide of herpes simplex virus type 1. Virology. 1974 Dec;62(2):539–551. doi: 10.1016/0042-6822(74)90414-0. [DOI] [PubMed] [Google Scholar]
  10. DeLuca N. A., Courtney M. A., Schaffer P. A. Temperature-sensitive mutants in herpes simplex virus type 1 ICP4 permissive for early gene expression. J Virol. 1984 Dec;52(3):767–776. doi: 10.1128/jvi.52.3.767-776.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. DeLuca N. A., McCarthy A. M., Schaffer P. A. Isolation and characterization of deletion mutants of herpes simplex virus type 1 in the gene encoding immediate-early regulatory protein ICP4. J Virol. 1985 Nov;56(2):558–570. doi: 10.1128/jvi.56.2.558-570.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. DeLuca N. A., Schaffer P. A. Activation of immediate-early, early, and late promoters by temperature-sensitive and wild-type forms of herpes simplex virus type 1 protein ICP4. Mol Cell Biol. 1985 Aug;5(8):1997–2008. doi: 10.1128/mcb.5.8.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. DeLuca N. A., Schaffer P. A. Activities of herpes simplex virus type 1 (HSV-1) ICP4 genes specifying nonsense peptides. Nucleic Acids Res. 1987 Jun 11;15(11):4491–4511. doi: 10.1093/nar/15.11.4491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. DeLuca N., Bzik D. J., Bond V. C., Person S., Snipes W. Nucleotide sequences of herpes simplex virus type 1 (HSV-1) affecting virus entry, cell fusion, and production of glycoprotein gb (VP7). Virology. 1982 Oct 30;122(2):411–423. doi: 10.1016/0042-6822(82)90240-9. [DOI] [PubMed] [Google Scholar]
  15. Dixon R. A., Schaffer P. A. Fine-structure mapping and functional analysis of temperature-sensitive mutants in the gene encoding the herpes simplex virus type 1 immediate early protein VP175. J Virol. 1980 Oct;36(1):189–203. doi: 10.1128/jvi.36.1.189-203.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Everett R. D. Trans activation of transcription by herpes virus products: requirement for two HSV-1 immediate-early polypeptides for maximum activity. EMBO J. 1984 Dec 20;3(13):3135–3141. doi: 10.1002/j.1460-2075.1984.tb02270.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Faber S. W., Wilcox K. W. Association of the herpes simplex virus regulatory protein ICP4 with specific nucleotide sequences in DNA. Nucleic Acids Res. 1986 Aug 11;14(15):6067–6083. doi: 10.1093/nar/14.15.6067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Faber S. W., Wilcox K. W. Characterization of a herpes simplex virus regulatory protein: aggregation and phosphorylation of a temperature-sensitive variant of ICP 4. Arch Virol. 1986;91(3-4):297–312. doi: 10.1007/BF01314289. [DOI] [PubMed] [Google Scholar]
  19. Gelman I. H., Silverstein S. Identification of immediate early genes from herpes simplex virus that transactivate the virus thymidine kinase gene. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5265–5269. doi: 10.1073/pnas.82.16.5265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Godowski P. J., Knipe D. M. Transcriptional control of herpesvirus gene expression: gene functions required for positive and negative regulation. Proc Natl Acad Sci U S A. 1986 Jan;83(2):256–260. doi: 10.1073/pnas.83.2.256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Goldberg D. A. Isolation and partial characterization of the Drosophila alcohol dehydrogenase gene. Proc Natl Acad Sci U S A. 1980 Oct;77(10):5794–5798. doi: 10.1073/pnas.77.10.5794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Holland L. E., Anderson K. P., Shipman C., Jr, Wagner E. K. Viral DNA synthesis is required for the efficient expression of specific herpes simplex virus type 1 mRNA species. Virology. 1980 Feb;101(1):10–24. doi: 10.1016/0042-6822(80)90479-1. [DOI] [PubMed] [Google Scholar]
  23. Honess R. W., Roizman B. Regulation of herpesvirus macromolecular synthesis. I. Cascade regulation of the synthesis of three groups of viral proteins. J Virol. 1974 Jul;14(1):8–19. doi: 10.1128/jvi.14.1.8-19.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jones K. A., Tjian R. Sp1 binds to promoter sequences and activates herpes simplex virus 'immediate-early' gene transcription in vitro. Nature. 1985 Sep 12;317(6033):179–182. doi: 10.1038/317179a0. [DOI] [PubMed] [Google Scholar]
  25. Kalderon D., Richardson W. D., Markham A. F., Smith A. E. Sequence requirements for nuclear location of simian virus 40 large-T antigen. Nature. 1984 Sep 6;311(5981):33–38. doi: 10.1038/311033a0. [DOI] [PubMed] [Google Scholar]
  26. Knipe D. M., Senechek D., Rice S. A., Smith J. L. Stages in the nuclear association of the herpes simplex virus transcriptional activator protein ICP4. J Virol. 1987 Feb;61(2):276–284. doi: 10.1128/jvi.61.2.276-284.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kristie T. M., Roizman B. Alpha 4, the major regulatory protein of herpes simplex virus type 1, is stably and specifically associated with promoter-regulatory domains of alpha genes and of selected other viral genes. Proc Natl Acad Sci U S A. 1986 May;83(10):3218–3222. doi: 10.1073/pnas.83.10.3218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kristie T. M., Roizman B. DNA-binding site of major regulatory protein alpha 4 specifically associated with promoter-regulatory domains of alpha genes of herpes simplex virus type 1. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4700–4704. doi: 10.1073/pnas.83.13.4700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  30. Mackem S., Roizman B. Structural features of the herpes simplex virus alpha gene 4, 0, and 27 promoter-regulatory sequences which confer alpha regulation on chimeric thymidine kinase genes. J Virol. 1982 Dec;44(3):939–949. doi: 10.1128/jvi.44.3.939-949.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Manservigi R., Spear P. G., Buchan A. Cell fusion induced by herpes simplex virus is promoted and suppressed by different viral glycoproteins. Proc Natl Acad Sci U S A. 1977 Sep;74(9):3913–3917. doi: 10.1073/pnas.74.9.3913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mavromara-Nazos P., Silver S., Hubenthal-Voss J., McKnight J. L., Roizman B. Regulation of herpes simplex virus 1 genes: alpha gene sequence requirements for transient induction of indicator genes regulated by beta or late (gamma 2) promoters. Virology. 1986 Mar;149(2):152–164. doi: 10.1016/0042-6822(86)90117-0. [DOI] [PubMed] [Google Scholar]
  33. McGeoch D. J., Dolan A., Donald S., Brauer D. H. Complete DNA sequence of the short repeat region in the genome of herpes simplex virus type 1. Nucleic Acids Res. 1986 Feb 25;14(4):1727–1745. doi: 10.1093/nar/14.4.1727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Morse L. S., Pereira L., Roizman B., Schaffer P. A. Anatomy of herpes simplex virus (HSV) DNA. X. Mapping of viral genes by analysis of polypeptides and functions specified by HSV-1 X HSV-2 recombinants. J Virol. 1978 May;26(2):389–410. doi: 10.1128/jvi.26.2.389-410.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Muller M. T. Binding of the herpes simplex virus immediate-early gene product ICP4 to its own transcription start site. J Virol. 1987 Mar;61(3):858–865. doi: 10.1128/jvi.61.3.858-865.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. O'Hare P., Hayward G. S. Comparison of upstream sequence requirements for positive and negative regulation of a herpes simplex virus immediate-early gene by three virus-encoded trans-acting factors. J Virol. 1987 Jan;61(1):190–199. doi: 10.1128/jvi.61.1.190-199.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. O'Hare P., Hayward G. S. Evidence for a direct role for both the 175,000- and 110,000-molecular-weight immediate-early proteins of herpes simplex virus in the transactivation of delayed-early promoters. J Virol. 1985 Mar;53(3):751–760. doi: 10.1128/jvi.53.3.751-760.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. O'Hare P., Hayward G. S. Three trans-acting regulatory proteins of herpes simplex virus modulate immediate-early gene expression in a pathway involving positive and negative feedback regulation. J Virol. 1985 Dec;56(3):723–733. doi: 10.1128/jvi.56.3.723-733.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Orberg P. K., Schaffer P. A. Expression of herpes simplex virus type 1 major DNA-binding protein, ICP8, in transformed cell lines: complementation of deletion mutants and inhibition of wild-type virus. J Virol. 1987 Apr;61(4):1136–1146. doi: 10.1128/jvi.61.4.1136-1146.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pereira L., Wolff M. H., Fenwick M., Roizman B. Regulation of herpesvirus macromolecular synthesis. V. Properties of alpha polypeptides made in HSV-1 and HSV-2 infected cells. Virology. 1977 Apr;77(2):733–749. doi: 10.1016/0042-6822(77)90495-0. [DOI] [PubMed] [Google Scholar]
  41. Post L. E., Mackem S., Roizman B. Regulation of alpha genes of herpes simplex virus: expression of chimeric genes produced by fusion of thymidine kinase with alpha gene promoters. Cell. 1981 May;24(2):555–565. doi: 10.1016/0092-8674(81)90346-9. [DOI] [PubMed] [Google Scholar]
  42. Post L. E., Roizman B. A generalized technique for deletion of specific genes in large genomes: alpha gene 22 of herpes simplex virus 1 is not essential for growth. Cell. 1981 Jul;25(1):227–232. doi: 10.1016/0092-8674(81)90247-6. [DOI] [PubMed] [Google Scholar]
  43. Preston C. M. Control of herpes simplex virus type 1 mRNA synthesis in cells infected with wild-type virus or the temperature-sensitive mutant tsK. J Virol. 1979 Jan;29(1):275–284. doi: 10.1128/jvi.29.1.275-284.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Preston V. G. Fine-structure mapping of herpes simplex virus type 1 temperature-sensitive mutations within the short repeat region of the genome. J Virol. 1981 Jul;39(1):150–161. doi: 10.1128/jvi.39.1.150-161.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Quinlan M. P., Knipe D. M. Stimulation of expression of a herpes simplex virus DNA-binding protein by two viral functions. Mol Cell Biol. 1985 May;5(5):957–963. doi: 10.1128/mcb.5.5.957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Sacks W. R., Greene C. C., Aschman D. P., Schaffer P. A. Herpes simplex virus type 1 ICP27 is an essential regulatory protein. J Virol. 1985 Sep;55(3):796–805. doi: 10.1128/jvi.55.3.796-805.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sacks W. R., Schaffer P. A. Deletion mutants in the gene encoding the herpes simplex virus type 1 immediate-early protein ICP0 exhibit impaired growth in cell culture. J Virol. 1987 Mar;61(3):829–839. doi: 10.1128/jvi.61.3.829-839.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Schröder C. H., DeZazzo J., Knopf K. W., Kaerner H. C., Levine M., Glorioso J. A herpes simplex virus type 1 mutant with a deletion in the polypeptide-coding sequences of the ICP4 gene. J Gen Virol. 1985 Jul;66(Pt 7):1589–1593. doi: 10.1099/0022-1317-66-7-1589. [DOI] [PubMed] [Google Scholar]
  49. Smith C. A., Schaffer P. A. Mutants defective in herpes simplex virus type 2 ICP4: isolation and preliminary characterization. J Virol. 1987 Apr;61(4):1092–1097. doi: 10.1128/jvi.61.4.1092-1097.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Weinheimer S. P., McKnight S. L. Transcriptional and post-transcriptional controls establish the cascade of herpes simplex virus protein synthesis. J Mol Biol. 1987 Jun 20;195(4):819–833. doi: 10.1016/0022-2836(87)90487-6. [DOI] [PubMed] [Google Scholar]
  51. Wilcox K. W., Kohn A., Sklyanskaya E., Roizman B. Herpes simplex virus phosphoproteins. I. Phosphate cycles on and off some viral polypeptides and can alter their affinity for DNA. J Virol. 1980 Jan;33(1):167–182. doi: 10.1128/jvi.33.1.167-182.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]

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