Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle

Hrecka, K., Gierszewska, M., Srivastava, S., Kozaczkiewicz, L., Swanson, S. K., Florens, L., Washburn, M. P., Skowronski, J. (July 2007) Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle. Proc Natl Acad Sci U S A, 104 (28). pp. 11778-83. ISSN 0027-8424 (Print)

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URL: https://www.ncbi.nlm.nih.gov/pubmed/17609381
DOI: 10.1073/pnas.0702102104


The replication of viruses depends on the cell cycle status of the infected cells. Viruses have evolved functions that alleviate restrictions imposed on their replication by the host. Vpr, an accessory factor of primate lentiviruses, arrests cells at the DNA damage checkpoint in G2 phase of the cell cycle, but the mechanism underlying this effect has remained elusive. Here we report that Vpr proteins of both the human (HIV-1) and the distantly related simian (SIVmac) immunodeficiency viruses specifically associate with a protein complex comprising subunits of E3 ubiquitin ligase assembled on Cullin-4 scaffold (Cul4-DDB1[VprBP]). We show that Vpr binding to Cul4-DDB1[VprBP] leads to increased neddylation and elevated intrinsic ubiquitin ligase activity of this E3. This effect is mediated through the VprBP subunit of the complex, which recently has been suggested to function as a substrate receptor for Cul4. We also demonstrate that VprBP regulates G1 phase and is essential for the completion of DNA replication in S phase. Furthermore, the ability of Vpr to arrest cells in G2 phase correlates with its ability to interact with Cul4-DDB1[VprBP] E3 complex. Our studies identify the Cul4-DDB1[VprBP] E3 ubiquitin ligase complex as the downstream effector of lentiviral Vpr for the induction of cell cycle arrest in G2 phase and suggest that Vpr may use this complex to perturb other aspects of the cell cycle and DNA metabolism in infected cells.

Item Type: Paper
Uncontrolled Keywords: Animals Carrier Proteins/metabolism Cell Cycle/ physiology Cell Line Cullin Proteins/ antagonists & inhibitors DNA-Binding Proteins/ metabolism Eukaryotic Initiation Factors/metabolism G2 Phase/physiology Gene Products, vpr/metabolism/ physiology HIV-1/ physiology Humans Protein Binding Protein Subunits/physiology Simian immunodeficiency virus/ physiology Ubiquitin-Protein Ligases/ antagonists & inhibitors
Subjects: diseases & disorders > viral diseases > HIV
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > VPR protein
organism description > virus > lentivirus
CSHL Authors:
Communities: CSHL labs > Skowronski lab
Depositing User: CSHL Librarian
Date: 10 July 2007
Date Deposited: 14 Nov 2011 16:59
Last Modified: 08 Nov 2017 22:10
PMCID: PMC1906728
Related URLs:
URI: https://repository.cshl.edu/id/eprint/23038

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