HIV-1 accessory protein Vpr inhibits the effect of insulin on the Foxo subfamily of forkhead transcription factors by interfering with their binding to 14-3-3 proteins: Potential clinical implications regarding the insulin resistance of HIV-1-infected patients

Tomoshige Kino, Massimo U. De Martino, Evangella Charmandari, Takamasa Ichijo, Taoufik Outas, George P. Chrousos

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HIV-1 accessory protein Vpr arrests host cells at the 62/M phase of the cell cycle by interacting with members of the protein family 14-3-3, which regulate the activities of "partner" molecules by binding to their phosphorylated serine or threonine residues and changing their intracellular localization and/or stability. Vpr does this by facilitating the association of 14-3-3 to its partner protein Cdc25C, independent of the latter's phosphorylation status. Here we report that the same viral protein interfered with and altered the activity of another 14-3-3 partner molecule, Foxo3a, a subtype of the forkhead transcription factors, by inhibiting its association with 14-3-3. Foxo3a's transcriptional activity is normally suppressed by insulin-induced translocatiori of this protein from the nucleus into the cytoplasm. Vpr inhibited the ability of insulin or its downstream protein kinase Akt to change the intracellular localization of Foxo3a preferentially to the cytoplasm. This HIV-1 protein also interfered with insulin-induced coprecipitation of 14-3-3 and Foxo3a in vivo and antagonized the negative effect of insulin on Foxo3a-induced transactivation of a FOXO-responsive promoter. Moreover, Vpr antagonized insulin-induced suppression of the mRNA expression of the glucose 6-phosphatase, manganese superoxide disirintase, and sterol carrier protein 2 genes, which are known targets of insulin and FOXO, in Hep62 cells. These findings indicate that Vpr interferes with the suppressive effects of insulin on FOXO-mediated transcription of target genes via 14-3-3. Vpr thus may contribute to the tissue-selective insulin resistance often observed in HIV-1-infected individuals.

Original languageEnglish
Pages (from-to)23-31
Number of pages9
Issue number1
Publication statusPublished - Jan 2005
Externally publishedYes


ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

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