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Journal of Virology, June 2007, p. 6459-6470, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.00380-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

US3 of Herpes Simplex Virus Type 1 Encodes a Promiscuous Protein Kinase That Phosphorylates and Alters Localization of Lamin A/C in Infected Cells{triangledown}

Fan Mou, Tom Forest,{dagger} and Joel D. Baines*

Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853

Received 22 February 2007/ Accepted 30 March 2007

The herpes simplex virus type 1 (HSV-1) US3 gene encodes a serine/threonine kinase that, when inactivated, causes capsids to aggregate aberrantly between the inner and outer nuclear membranes (INM and ONM, respectively) within evaginations/extensions of the perinuclear space. In both Hep2 cells and an engineered cell line derived from Hep2 cells expressing lamin A/C fused to enhanced green fluorescent protein (eGFP-lamin A/C), lamin A/C localized mostly in a reticular pattern with small regions of the INM devoid of eGFP-lamin A/C when they were either mock infected or infected with wild-type HSV-1(F). Cells infected with HSV-1(F) also contained some larger diffuse regions lacking lamin A/C. Proteins UL31 and UL34, markers of potential envelopment sites at the INM and perinuclear virions, localized within the regions devoid of lamin A/C and also in regions containing lamin A/C. Similar to previous observations with Vero cells (S. L. Bjerke and R. J. Roller, Virology 347:261-276, 2006), the proteins UL34 and UL31 localized exclusively in very discrete regions of the nuclear lamina lacking lamin A/C in the absence of US3 kinase activity. To determine how US3 alters lamin A/C distribution, US3 was purified and shown to phosphorylate lamin A/C at multiple sites in vitro, despite the presence of only one putative US3 kinase consensus site in the lamin A/C sequence. US3 kinase activity was also sufficient to invoke partial solubilization of lamin A/C from permeabilized Hep2 cell nuclei in an ATP-dependent manner. Two-dimensional electrophoretic analyses of lamin A/C revealed that lamin A/C is phosphorylated in HSV-infected cells, and the full spectrum of phosphorylation requires US3 kinase activity. These data suggest that US3 kinase activity regulates HSV-1 capsid nuclear egress at least in part by phosphorylation of lamin A/C.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, C5143 Veterinary Education Center, Cornell University, Ithaca, NY 14853. Phone: (607) 253-3391. Fax: (607) 253-3384. E-mail: jdb11{at}cornell.edu

{triangledown} Published ahead of print on 11 April 2007.

{dagger} Present address: Merck and Company, Lancaster, PA.

Journal of Virology, June 2007, p. 6459-6470, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.00380-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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