Hyperglycemia-Induced O-GlcNAcylation and Truncation of 4E-BP1 Protein in Liver of a Mouse Model of Type 1 Diabetes

• Published in: The Journal of biological chemistry Vol. 286; no. 39; pp. 34286 - 34297
• Main Authors: Dennis, Michael D., Schrufer, Tabitha L., Bronson, Sarah K., Kimball, Scot R., Jefferson, Leonard S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.09.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Acetylglucosamine - genetics; Acetylglucosamine - metabolism; Adaptor Proteins, Signal Transducing; Animals; Blood Glucose - genetics; Blood Glucose - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Cycle Proteins; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Disease Models, Animal; eIF4E; eIF4E Binding Protein 1; Eukaryotic Initiation Factors; Glycosylation; Glycosylation - drug effects; Hyperglycemia; Hyperglycemia - genetics; Hyperglycemia - metabolism; Liver - metabolism; Mice; Mice, Transgenic; O-linked Glycosylation; Phlorhizin - pharmacology; Phosphoproteins - genetics; Phosphoproteins - metabolism; Post-translational Modification; Protein Synthesis and Degradation; Protein Truncation; Translation Initiation Factors; Translation Regulation; eIF4E Binding Protein 1; Protein Truncation; eIF4E; Hyperglycemia; Translation Regulation; Post-translational Modification; O-linked Glycosylation; Glycosylation; Diabetes; Translation Initiation Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.259457

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, 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 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. Background: Covalent modification of mRNA translation initiation factors regulates gene expression. Result: The translational repressor 4E-BP1 is covalently modified by O-GlcNAcylation. Conclusion: The function of 4E-BP1 is regulated not only by phosphorylation but also by O-GlcNAcylation. Significance: These findings reveal a novel mechanism through which hyperglycemia-mediated 4E-BP1 O-GlcNAcylation represses cap-dependent mRNA translation and protein synthesis.