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.
HIV-1 accessory protein Vpr arrests host cells at the G2/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 translocation 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 dismutase, and sterol carrier protein 2 genes, which are known targets of insulin and FOXO, in HepG2 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.
Kino
Tomoshige
T
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, NIH, 10 Center Dr. MSC 1109, Building 10, Clinical Research Center, Room 1-3140, Bethesda, MD 20892-1109, USA. kinot@mail.nih.gov
De Martino
Massimo U
MU
Charmandari
Evangelia
E
Ichijo
Takamasa
T
Outas
Taoufik
T
Chrousos
George P
GP
D048948:14-3-3 Proteins / Q000378:metabolism*; D000163:Acquired Immunodeficiency Syndrome / Q000503:physiopathology*; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005656:Fungal Proteins; D016336:Gene Products, vpr / Q000494:pharmacology*; D015658:HIV Infections / Q000503:physiopathology*; D015497:HIV-1; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007329:Insulin Antagonists / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D006899:Mixed Function Oxygenases; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014162:Transfection; D014764:Viral Proteins / Q000494:pharmacology; D054325:vpr Gene Products, Human Immunodeficiency Virus
D048948:14-3-3 Proteins; D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005656:Fungal Proteins; D016336:Gene Products, vpr; D007328:Insulin; D007329:Insulin Antagonists; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D014764:Viral Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt