14-3-3 theta binding to cell cycle regulatory factors is enhanced by HIV-1 Vpr

Diane L Bolton¹^,2 , Robert A Barnitz¹ , Keiko Sakai¹^,3 and Michael J Lenardo¹

¹Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, MD, 20892, USA

²ImmunoTechnology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

³Division of Viral Immunology, Center for AIDS Research, Kumamoto University, Kumamoto, Japan

author email corresponding author email

Biology Direct 2008, 3:17doi:10.1186/1745-6150-3-17


Published:	29 April 2008

Abstract

Background

Despite continuing advances in our understanding of AIDS pathogenesis, the mechanism of CD4+ T cell depletion in HIV-1-infected individuals remains unclear. The HIV-1 Vpr accessory protein causes cell death, likely through a mechanism related to its ability to arrest cells in the G₂,M phase. Recent evidence implicated the scaffold protein, 14-3-3, in Vpr cell cycle blockade.

Results

We found that in human T cells, 14-3-3 plays an active role in mediating Vpr-induced cell cycle arrest and reveal a dramatic increase in the amount of Cdk1, Cdc25C, and CyclinB1 bound to 14-3-3 θ during Vpr_v-induced G₂,M arrest. By contrast, a cell-cycle-arrest-dead Vpr mutant failed to augment 14-3-3 θ association with Cdk1 and CyclinB1. Moreover, G₂,M arrest caused by HIV-1 infection strongly correlated with a disruption in 14-3-3 θ binding to centrosomal proteins, Plk1 and centrin. Finally, Vpr caused elevated levels of CyclinB1, Plk1, and Cdk1 in a complex with the nuclear transport and spindle assembly protein, importin β.

Conclusion

Thus, our data reveal a new facet of Vpr-induced cell cycle arrest involving previously unrecognized abnormal rearrangements of multiprotein assemblies containing key cell cycle regulatory proteins.

Reviewers

This article was reviewed by David Kaplan, Nathaniel R. Landau and Yan Zhou.