JVI Accepts, published online ahead of print on 17 October 2007

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J. Virol. doi:10.1128/JVI.02010-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Accumulation of Substrates of the Anaphase-Promoting Complex (APC) During Human Cytomegalovirus Infection is Associated with the Phosphorylation of Cdh1 and the Dissociation and Relocalization of the APC Subunits

Karen Tran, Jeffrey A. Mahr, Jiwon Choi, Jose G. Teodoro, Michael R. Green, and Deborah H. Spector^*

Department of Cellular and Molecular Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093-0712, and Howard Hughes Medical Institute and Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605

^* To whom correspondence should be addressed. Email: dspector{at}ucsd.edu.

Cell cycle dysregulation upon human cytomegalovirus (HCMV) infection of human fibroblasts is associated with the inactivation of the Anaphase-Promoting Complex (APC), a multi-subunit E3 ubiquitin ligase, and accumulation of its substrates. Here, we have further elucidated the mechanism(s) by which HCMV-induced inactivation of the APC occurs. Our results show that Cdh1 accumulates in a phosphorylated form that may prevent its association with and activation of the APC. The accumulation of Cdh1, but not its phosphorylation, appears to be CDK-dependent. Lack of association of exogenously added Cdh1 with the APC from infected cells indicates that the core APC may also be impaired. This is further supported by the examination of the localization and composition of the APC. Co-immunoprecipitation studies show that both Cdh1 and the subunit APC1 become dissociated from the complex. In addition, immunofluorescence analysis demonstrates that as the infection progresses, several subunits redistribute to the cytoplasm, while APC1 remains nuclear. Dissociation of the core complex itself would account for not only the observed inactivity, but also its inability to bind to Cdh1. Taken together, these results illustrate that HCMV has adopted multiple mechanisms to inactivate the APC, which underscores its importance for a productive infection.

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