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

Abstract

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.

Whole-Body Proteolysis Rate Is Elevated in HIV-Associated Insulin Resistance

“…HIVϩIGT subjects had several features of hypercortisolism including higher visceral adipose area, hepatic steatosis, and glucose intolerance; however, plasma cortisol levels were not different among groups. Viral protein R acts as a coactivator of the human glucocorticoid receptor, and it is possible that this might link the features of hypercortisolism with HIVϩIGT subjects (31). However, this would not explain the differences in leucine metabolism between the two HIV-infected groups.…”

“…Our findings suggest that there may be a defect in the insulin signaling pathway, which is common to the regulation of both glucose and BCAA metabolism. Possibilities might include insulin-induced intramyocellular kinase activation cascades that regulate protein synthesis (e.g., Akt, glycogen synthase kinase 3␤, mTOR, p70 s6kinase , elongation-initiation factors-2B and -4E, and 4E-binding protein-1) and protein breakdown (Forkhead transcription factors [31], nuclear factor-B, ubiquitin-proteasome pathway, atrogin, and myostatin). A role for these factors in the pathogenesis of HIVϩIGT subjects needs to be examined further.…”

Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

“…Akt can phosphorylate FoxO3a and inhibit its activity to sequester FoxO3a in the cytoplasm by association with 14-3-3 proteins (Brunet et al, 2002;Dong et al, 2007;Kino et al, 2005;Munoz-Fontela et al, 2007). In the absence of inhibitory Akt1 phosphorylation, FoxO3a can translocate to the nucleus, and controls a variety of functions that involve cell cycle progression, cell longevity, and apoptosis (Lehtinen et al, 2006;Li et al, 2006a;Maiese et al, 2007a).…”

Lipodystrophy in HIV 1-infected patients: lessons for obesity research

“…73,74 Although no studies have 73,75 Recently available transgenic mice expressing the HIV-1 Vpr protein in adipose tissues and in the liver show altered systemic lipid metabolism. 76 Vpr is also a known inducer of apoptosis through activation of the mitochondrial permeability transition pore (MPTP) 77 and therefore may contribute to adipocyte apoptosis in HALS, although this issue has not yet been addressed in adipose cells.…”