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J. Virol., 03 1997, 1757-1765, Vol 71, No. 3
Copyright © 1997, American Society for Microbiology

Identification of a promoter-specific transactivation domain in the herpes simplex virus regulatory protein ICP4

W Xiao, LI Pizer and KW Wilcox
Department of Microbiology, Medical College of Wisconsin, Milwaukee 53226, USA.

ICP4 is expressed during the immediate-early phase of infection by herpes simplex virus (HSV) and activates transcription of viral genes during subsequent phases of productive infection. Several members of the alpha-herpesvirus family encode regulatory proteins that have extensive homology with ICP4 and exhibit a transactivation domain (TAD) at the N terminus. The portions of ICP4 required for nuclear localization, DNA binding, and dimerization have been defined, but a domain that is specifically required for transactivation has not been identified. We have defined a promoter-specific ICP4 TAD by analysis of the activity of GAL4-ICP4 fusion proteins cotransfected into HeLa cells with a luciferase reporter gene linked to a promoter with five GAL4 binding sites. The transactivation activity of GAL4-ICP4 hybrids is located entirely within the first 139 residues of ICP4 and is significantly less potent than the activity of GAL4-TAD hybrids derived from ICP4 homologs. ICP4 residues 97 to 109 are a critical component of this N-terminal TAD. Transient transfection assays performed with nonfusion forms of ICP4 and luciferase genes linked to the HSV glycoprotein D (gD) or thymidine kinase (tk) promoter revealed that ICP4 residues 97 to 109 are required for induction of the gD promoter but are not required for induction of the tk promoter. Comparative experiments with ICP4 homologs revealed that the pseudorabies virus TAD is a potent activator of the gD promoter and a weak activator of the tk promoter. Complementation assays revealed that loss of ICP4 residues 97 to 109 reduced the yield of virus from infected cells nearly 500-fold compared to wild-type ICP4. We conclude that ICP4 residues 97 to 109 are a core component of a promoter-specific transactivation domain that is required for efficient replication of herpes simplex virus.

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