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, Alexander Gragerov, Antonio Valentin, Maria Tsopanomihalou, Galina Ilyina-Gragerova, Rebecca Erwin-Cohen, George P. Chrousos, George N. Pavlakis

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Abstract

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 14-3-3σ. 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.

Original languageEnglish
Pages (from-to)2780-2787
Number of pages8
JournalJournal of Virology
Volume79
Issue number5
DOIs
Publication statusPublished - Mar 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology

Cite this

Kino, T., Gragerov, A., Valentin, A., Tsopanomihalou, M., Ilyina-Gragerova, G., Erwin-Cohen, R., Chrousos, G. P., & Pavlakis, G. N. (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. Journal of Virology, 79(5), 2780-2787. https://doi.org/10.1128/JVI.79.5.2780-2787.2005