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Journal of Virology, November 2000, p. 10417-10429, Vol. 74, No. 22
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Ras-GAP Binding and Phosphorylation by Herpes Simplex Virus Type 2 RR1 PK (ICP10) and Activation of the Ras/MEK/MAPK Mitogenic Pathway Are Required for Timely Onset of Virus Growth

C. C. Smith,1 J. Nelson,1,dagger L. Aurelian,1,2,* M. Gober,1 and B. B. Goswami3

Departments of Pharmacology and Experimental Therapeutics1 and Microbiology,2 University of Maryland School of Medicine, Baltimore, Maryland 21201, and FDA Center for Food Safety and Applied Nutrition, Washington, D.C. 202043

Received 9 May 2000/Accepted 22 August 2000

We used a herpes simplex virus type 2 (HSV-2) mutant with a deletion in the RR1 (ICP10) PK domain (ICP10Delta PK) and an MEK inhibitor (PD98059) to examine the role of ICP10 PK in virus growth. In HSV-2-infected cells, ICP10 PK binds and phosphorylates the GTPase activating protein Ras-GAP. In vitro binding and peptide competition assays indicated that Ras-GAP N-SH2 and PH domains, respectively, bind ICP10 at phosphothreonines 117 and 141 and a WD40-like motif at positions 160 to 173. Binding and phosphorylation did not occur in cells infected with ICP10Delta PK. GTPase activity was significantly lower in HSV-2- than in ICP10Delta PK-infected cells. Conversely, the levels of activated Ras and mitogen-activated protein kinase (MAPK), and the expression and stabilization of the transcription factor c-Fos were significantly increased in cells infected with HSV-2 or a revertant virus [HSV-2(R)] but not with ICP10Delta PK. PD98059 inhibited MAPK activation and induction-stabilization of c-Fos. Expression from the ICP10 promoter was increased in cells infected with HSV-2 but not with ICP10Delta PK, and increased expression was ablated by PD98059. ICP10 DNA formed a complex with nuclear extracts from HSV-2-infected cells which was supershifted by c-Fos antibody and was not seen with extracts from ICP10Delta PK-infected cells. Complex formation was abrogated by PD98059. Onset of HSV-2 replication was significantly delayed by PD98059 (14 h versus 2 h in untreated cells), a delay similar to that seen for ICP10Delta PK. The data indicate that Ras-GAP phosphorylation by ICP10 PK is involved in the activation of the Ras/MEK/MAPK mitogenic pathway and c-Fos induction and stabilization. This results in increased ICP10 expression and the timely onset of HSV-2 growth.

* Corresponding author. Mailing address: Virology/Immunology Laboratories, School of Medicine, University of Maryland at Baltimore, 10 S. Pine St., Room 500-F, Baltimore, MD 21201-1192. Phone: (410) 706-3895. Fax: (410) 706-2513. E-mail: laurelia{at}umaryland.edu.

dagger Present address: American Association for the Advancement of Science, Washington, DC 20005.

Journal of Virology, November 2000, p. 10417-10429, Vol. 74, No. 22
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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