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Herpes Simplex Virus Type 1 ICP27-Dependent Activation of NF-B

Danna Hargett,^1, Stephen Rice,³ and Steven L. Bachenheimer^1,2*

Department of Microbiology and Immunology,¹ Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7290,² Department of Microbiology, University of Minnesota Medical School, 420 Delaware Street SE, Mayo Mail Code 196, Minneapolis, Minnesota 55455³

Received 31 May 2006/ Accepted 11 August 2006

The ability of herpes simplex virus type 1 (HSV-1) to activate NF-B has been well documented. Beginning at 3 to 5 h postinfection, HSV-1 induces a robust and persistent nuclear translocation of an NF-B-dependent (p50/p65 heterodimer) DNA binding activity, as measured by electrophoretic mobility shift assay. Activation requires virus binding and entry, as well as de novo infected-cell protein synthesis, and is accompanied by loss of both IB and IBß. In this study, we identified loss of IB as a marker of NF-B activation, and infection with mutants with individual immediate-early (IE) regulatory proteins deleted indicated that ICP27 was necessary for IB loss. Analysis of both N-terminal and C-terminal mutants of ICP27 identified the region from amino acids 21 to 63 as being necessary for IB loss. Additional experiments with mutant viruses with combinations of IE genes deleted revealed that the ICP27-dependent mechanism of NF-B activation may be augmented by functional ICP4. We also analyzed two additional markers for NF-B activation, phosphorylation of the p65 subunit on Ser276 and Ser536. Phosphorylation of both serines was induced upon HSV infection and required functional ICP4 and ICP27. Pharmacological inhibitor studies revealed that both IB and Ser276 phosphorylation were dependent on Jun N-terminal protein kinase activity, while Ser536 phosphorylation was not affected during inhibitor treatment. These results demonstrate that there are several layers of regulation of NF-B activation during HSV infection, highlighting the important role that NF-B may play in infection.

Published ahead of print on 23 August 2006.

Present address: Lewis Thomas Lab, Department of Molecular Biology, Princeton University, Washington Rd., Princeton, NJ 08544-1014.

This article has been cited by other articles:

• Sedlackova, L., Rice, S. A. (2008). Herpes Simplex Virus Type 1 Immediate-Early Protein ICP27 Is Required for Efficient Incorporation of ICP0 and ICP4 into Virions. J. Virol. 82: 268-277 [Abstract] [Full Text]