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J. Biol. Chem., Vol. 282, Issue 37, 27046-27057, September 14, 2007

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The HIV1 Protein Vpr Acts to Promote G₂ Cell Cycle Arrest by Engaging a DDB1 and Cullin4A-containing Ubiquitin Ligase Complex Using VprBP/DCAF1 as an Adaptor^*

From the Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208

The roles of the HIV1 protein Vpr in virus replication and pathogenesis remain unclear. Expression of Vpr in dividing cells causes cell cycle arrest in G₂. Vpr also facilitates low titer infection of terminally differentiated macrophages, enhances transcription, promotes apoptosis, and targets cellular uracil N-glycosylase for degradation. Using co-immunoprecipitation and tandem mass spectroscopy, we found that HIV1 Vpr engages a DDB1- and cullin4A-containing ubiquitin-ligase complex through VprBP/DCAF1. HIV2 Vpr has two Vpr-like proteins, Vpr and Vpx, which cause G₂ arrest and facilitate macrophage infection, respectively. HIV2 Vpr, but not Vpx, engages the same set of proteins. We further demonstrate that the interaction between Vpr and the ubiquitin-ligase components as well as further assembly of the ubiquitin-ligase are necessary for Vpr-mediated G₂ arrest. Our data support a model in which Vpr engages the ubiquitin ligase to deplete a cellular factor that is required for cell cycle progression into mitosis. Vpr, thus, functions like the HIV1 proteins Vif and Vpu to usurp cellular ubiquitin ligases for viral functions.

Received for publication, May 14, 2007 , and in revised form, June 26, 2007.

^* This work was supported by Albany Medical College start-up funds and an Albany Medical College bridge grant (to C. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Medical Sciences Bldg. 216, MC-151, Albany Medical College, Albany, NY 12208. Tel.: 518-262-1175; Fax: 518-262-6161; E-mail: DeNoroC{at}mail.AMC.edu.

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