Abstract
4E-BP1 is a protein that, in its hypophosphorylated state, binds the mRNA cap-binding protein eIF4E and represses cap-dependent mRNA translation. By doing so, it plays a major role in the regulation of gene expression by controlling the overall rate of mRNA translation as well as the selection of mRNAs for translation. Phosphorylation of 4E-BP1 causes it to release eIF4E to function in mRNA translation. 4E-BP1 is also subject to covalent addition of N-acetylglucosamine to Ser or Thr residues (O-GlcNAcylation) as well as to truncation. In the truncated form, it is both resistant to phosphorylation and able to bind eIF4E with high affinity. In the present study, Ins2(Akita/+) diabetic mice were used to test the hypothesis that hyperglycemia and elevated flux of glucose through the hexosamine biosynthetic pathway lead to increased O-GlcNAcylation and truncation of 4E-BP1 and consequently decreased eIF4E function in the liver. The amounts of both full-length and truncated 4E-BP1 bound to eIF4E were significantly elevated in the liver of diabetic as compared with non-diabetic mice. In addition, O-GlcNAcylation of both the full-length and truncated proteins was elevated by 2.5- and 5-fold, respectively. Phlorizin treatment of diabetic mice lowered blood glucose concentrations and reduced the expression and O-GlcNAcylation of 4E-BP1. Additionally, when livers were perfused in the absence of insulin, 4E-BP1 phosphorylation in the livers of diabetic mice was normalized to the control value, yet O-GlcNAcylation and the association of 4E-BP1 with eIF4E remained elevated in the liver of diabetic mice. These findings provide insight into the pathogenesis of metabolic abnormalities associated with diabetes.
Highlights
Covalent modification of mRNA translation initiation factors regulates gene expression
Ins2Akita/ϩ mice were used as a model of type 1 diabetes to evaluate the hypothesis that in the liver of diabetic mice elevated flux of glucose through the hexosamine biosynthetic pathway leads to increased O-GlcNAcylation and concomitant reduced phosphorylation of 4E-BP1 resulting in increased association with eIF4E
Our results explore the regulation of 4E-BP1 in the liver of diabetic mice and provide evidence for a model wherein hyperglycemiadriven 4E-BP1 O-GlcNAcylation could inhibit cap-dependent mRNA translation and protein synthesis
Summary
Covalent modification of mRNA translation initiation factors regulates gene expression. Ins2Akita/؉ diabetic mice were used to test the hypothesis that hyperglycemia and elevated flux of glucose through the hexosamine biosynthetic pathway lead to increased O-GlcNAcylation and truncation of 4E-BP1 and decreased eIF4E function in the liver. The increased binding to eIF4E is due to a reduction in phosphorylation of 4E-BP1 resulting from diminished mTORC1 signaling in response to the deficiency of insulin Another mechanism that could account for the diabetes-induced increase in the association of 4E-BP1 with eIF4E is the addition of N-acetylglucosamine to serine or threonine residues (O-GlcNAcylation) at or near some specific phosphorylation site(s) (5). Ins2Akita/ϩ mice were used as a model of type 1 diabetes to evaluate the hypothesis that in the liver of diabetic mice elevated flux of glucose through the hexosamine biosynthetic pathway leads to increased O-GlcNAcylation and concomitant reduced phosphorylation of 4E-BP1 resulting in increased association with eIF4E. Our results explore the regulation of 4E-BP1 in the liver of diabetic mice and provide evidence for a model wherein hyperglycemiadriven 4E-BP1 O-GlcNAcylation could inhibit cap-dependent mRNA translation and protein synthesis
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