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Journal of Virology, November 2008, p. 10647-10656, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01063-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus Type 1 ICP0 Phosphorylation Mutants Impair the E3 Ubiquitin Ligase Activity of ICP0 in a Cell Type-Dependent Manner{triangledown}

Chris Boutell,1 Roger Everett,1 Joshua Hilliard,2 Priscilla Schaffer,3 Anne Orr,1 and David Davido2*

MRC Virology Unit, Institute of Virology, Church Street, Glasgow G11 5JR, Scotland, United Kingdom,1 Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045,2 Department of Molecular and Cellular Biology, University of Arizona, Tempe, Arizona 857213

Received 20 May 2008/ Accepted 13 August 2008

Herpes simplex virus type 1 (HSV-1) infected cell protein 0 (ICP0) is a 110-kDa nuclear phosphoprotein that is required for both the efficient initiation of lytic infection and the reactivation of quiescent viral genomes from latency. The ability of ICP0 to act as a potent viral transactivator is mediated by its N-terminal zinc-binding RING finger domain. This domain confers E3 ubiquitin ligase activity to ICP0 and is required for the proteasome-dependent degradation of a number of cellular proteins during infection, including the major nuclear domain 10 (ND10) constituent protein promyelocytic leukemia. In previous work we mapped three phosphorylation regions within ICP0, two of which directly affected its transactivation capabilities in transient transfection assays (Davido et al., J. Virol. 79:1232-1243, 2005). Because ICP0 is a phosphoprotein, we initially sought to test the hypothesis that phosphorylation regulates the E3 ubiquitin ligase activity of ICP0. Although none of the mutations affected ICP0 E3 ligase activity in vitro, transient transfection analysis indicated that mutations within one or more of the phosphorylated regions impaired the ability of ICP0 to form foci with colocalizing conjugated ubiquitin and to disrupt ND10. Mutations within one of the regions also affected ICP0 stability, and all of these phenomena occurred in a cell type-dependent manner. In the context of viral infection, only one ICP0 phosphorylation mutant (P1) showed a significant defect in viral replication and enhanced protein stability compared to all the other viruses tested. This study suggests that specific cellular environments and context of expression (transfection versus infection) differentially regulate several activities of ICP0 related to its E3 ubiquitin ligase activity via phosphorylation.

* Corresponding author. Mailing address: University of Kansas, 1200 Sunnyside Avenue, 7047 Haworth Hall, Lawrence, KS 66045. Phone: (785) 864-4022. Fax: (785) 864-5294. E-mail: ddavido{at}ku.edu

{triangledown} Published ahead of print on 20 August 2008.

Journal of Virology, November 2008, p. 10647-10656, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01063-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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