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Journal of Virology, March 2005, p. 2780-2787, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2780-2787.2005

Vpr Protein of Human Immunodeficiency Virus Type 1 Binds to 14-3-3 Proteins and Facilitates Complex Formation with Cdc25C: Implications for Cell Cycle Arrest

Tomoshige Kino,1,2 Alexander Gragerov,1 Antonio Valentin,1 Maria Tsopanomihalou,1 Galina Ilyina-Gragerova,1 Rebecca Erwin-Cohen,1 George P. Chrousos,2 and George N. Pavlakis1*

Human Retrovirus Section, Center for Cancer Research, National Cancer Institute—Frederick, Frederick,1 Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland2

Received 11 June 2004/ Accepted 20 October 2004

Vpr and selected mutants were used in a Saccharomyces cerevisiae two-hybrid screen to identify cellular interactors. We found Vpr interacted with 14-3-3 proteins, a family regulating a multitude of proteins in the cell. Vpr mutant R80A, which is inactive in cell cycle arrest, did not interact with 14-3-3. 14-3-3 proteins regulate the G2/M transition by inactivating Cdc25C phosphatase via binding to the phosphorylated serine residue at position 216 of Cdc25C. 14-3-3 overexpression in human cells synergized with Vpr in the arrest of cell cycle. Vpr did not arrest efficiently cells not expressing 14-3-3{sigma}. This indicated that a full complement of 14-3-3 proteins is necessary for optimal Vpr function on the cell cycle. Mutational analysis showed that the C-terminal portion of Vpr, known to harbor its cell cycle-arresting activity, bound directly to the C-terminal part of 14-3-3, outside of its phosphopeptide-binding pocket. Vpr expression shifted localization of the mutant Cdc25C S216A to the cytoplasm, indicating that Vpr promotes the association of 14-3-3 and Cdc25C, independently of the presence of serine 216. Immunoprecipitations of cell extracts indicated the presence of triple complexes (Vpr/14-3-3/Cdc25C). These results indicate that Vpr promotes cell cycle arrest at the G2/M phase by facilitating association of 14-3-3 and Cdc25C independently of the latter's phosphorylation status.

* Corresponding author. Mailing address: Human Retrovirus Section, Center for Cancer Research, National Cancer Institute—Frederick, Bldg. 535, Rm. 210, Frederick, MD 21702-1201. Phone: (301) 846-1474. Fax: (301) 846-6368. E-mail: pavlakis{at}ncifcrf.gov.

Journal of Virology, March 2005, p. 2780-2787, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2780-2787.2005




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