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

Proceedings of the National Academy of Sciences of the United States of America - Tập 104 Số 28 - Trang 11778-11783 - 2007
Kasia Hrecka1, Magdalena Gierszewska2, Smita Srivastava2, Lukasz Kozaczkiewicz2, Selene K. Swanson3,4, Laurence Florens3,4, Michael P. Washburn3,4, Jacek Skowroński2
1Cold Spring Harbor Laboratory, Bungtown Road, Cold Spring Harbor, NY 11724, USA.
2*Cold Spring Harbor Laboratory, Bungtown Road, Cold Spring Harbor, NY 11724; and
3Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110
4Stowers Institute for Medical Research,

Tóm tắt

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 G 2 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 G 1 phase and is essential for the completion of DNA replication in S phase. Furthermore, the ability of Vpr to arrest cells in G 2 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 G 2 phase and suggest that Vpr may use this complex to perturb other aspects of the cell cycle and DNA metabolism in infected cells.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 104 Số 28

11778-11783

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