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Journal of Virology, August 2008, p. 8094-8104, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00874-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Effects of Lamin A/C, Lamin B1, and Viral US3 Kinase Activity on Viral Infectivity, Virion Egress, and the Targeting of Herpes Simplex Virus UL34-Encoded Protein to the Inner Nuclear Membrane {triangledown}

Fan Mou, Elizabeth G. Wills, Richard Park, and Joel D. Baines*

Department of Microbiology and Immunology, New York State College of Veterinary Medicine, Cornell University, Ithaca, New York 14853

Received 24 April 2008/ Accepted 28 May 2008

Previous results indicated that the UL34 protein (pUL34) of herpes simplex virus 1 (HSV-1) is targeted to the nuclear membrane and is essential for nuclear egress of nucleocapsids. The normal localization of pUL34 and virions requires the US3-encoded kinase that phosphorylates UL34 and lamin A/C. Moreover, pUL34 was shown to interact with lamin A in vitro. In the present study, glutathione S-transferase/pUL34 was shown to specifically pull down lamin A and lamin B1 from cellular lysates. To determine the role of these interactions on viral infectivity and pUL34 targeting to the inner nuclear membrane (INM), the localization of pUL34 was determined in LmnA–/– and LmnB1–/– mouse embryonic fibroblasts (MEFs) by indirect immunofluorescence and immunogold electron microscopy in the presence or absence of US3 kinase activity. While pUL34 INM targeting was not affected by the absence of lamin B1 in MEFs infected with wild-type HSV as viewed by indirect immunofluorescence, it localized in densely staining scalloped-shaped distortions of the nuclear membrane in lamin B1 knockout cells infected with a US3 kinase-dead virus. Lamin B1 knockout cells were relatively less permissive for viral replication than wild-type MEFs, with viral titers decreased at least 10-fold. The absence of lamin A (i) caused clustering of pUL34 in the nuclear rim of cells infected with wild-type virus, (ii) produced extensions of the INM bearing pUL34 protein in cells infected with a US3 kinase-dead mutant, (iii) precluded accumulation of virions in the perinuclear space of cells infected with this mutant, and (iv) partially restored replication of this virus. The latter observation suggests that lamin A normally impedes viral infectivity and that US3 kinase activity partially alleviates this impediment. On the other hand, lamin B1 is necessary for optimal viral replication, probably through its well-documented effects on many cellular pathways. Finally, neither lamin A nor B1 was absolutely required for targeting pUL34 to the INM, suggesting that this targeting is mediated by redundant functions or can be mediated by other proteins.

* Corresponding author. Mailing address: C5169 Vet Med 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 4 June 2008.

Journal of Virology, August 2008, p. 8094-8104, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00874-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wisner, T. W., Wright, C. C., Kato, A., Kawaguchi, Y., Mou, F., Baines, J. D., Roller, R. J., Johnson, D. C. (2009). Herpesvirus gB-Induced Fusion between the Virion Envelope and Outer Nuclear Membrane during Virus Egress Is Regulated by the Viral US3 Kinase. J. Virol. 83: 3115-3126 [Abstract] [Full Text]  


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