Glucose Deprivation Stimulates O-GlcNAc Modification of Proteins through Up-regulation of O-Linked N-Acetylglucosaminyltransferase
| Autor: | Donald A. McClain, Rodrick P. Taylor, William Fuller, Marla J. Yazzie, Yudi Soesanto, Glendon J. Parker, Mark Hazel |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Glycosylation Time Factors Nutrient sensing Biology Carbohydrate metabolism N-Acetylglucosaminyltransferases Biochemistry Acetylglucosamine chemistry.chemical_compound Downregulation and upregulation Glucosamine Cell Line Tumor Internal medicine medicine Humans Glycogen synthase Molecular Biology Messenger RNA Cell Biology Glucose Glycogen Synthase Endocrinology chemistry Cell culture biology.protein Protein Processing Post-Translational |
| Zdroj: | Journal of Biological Chemistry. 283:6050-6057 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m707328200 |
| Popis: | O-Linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification of proteins that functions as a nutrient sensing mechanism. Here we report on regulation of O-GlcNAcylation over a broad range of glucose concentrations. We have discovered a significant induction of O-GlcNAc modification of a limited number of proteins under conditions of glucose deprivation. Beginning 12 h after treatment, glucose-deprived human hepatocellular carcinoma (HepG2) cells demonstrate a 7.8-fold increase in total O-GlcNAc modification compared with cells cultured in normal glucose (5 mm; p = 0.008). Some of the targets of glucose deprivation-induced O-GlcNAcylation are distinct from those modified in response to high glucose (20 mm) or glucosamine (10 mm) treatment, suggesting differential targeting with glucose deprivation and glucose excess. O-GlcNAcylation of glycogen synthase is significantly increased with glucose deprivation, and this O-GlcNAc increase contributes to a 60% decrease (p = 0.004) in glycogen synthase activity. Increased O-GlcNAc modification is not mediated by increased UDP-GlcNAc, the rate-limiting substrate for O-GlcNAcylation. Rather, the mRNA for nucleocytoplasmic O-linked N-acetylglucosaminyltransferase (OGT) increases 3.4-fold within 6 h of glucose deprivation (p = 0.006). Within 12 h, OGT protein increases 1.7-fold (p = 0.01) compared with normal glucose-treated cells. In addition, 12-h glucose deprivation leads to a 49% decrease in O-GlcNAcase protein levels (p = 0.03). We conclude that increased O-GlcNAc modification stimulated by glucose deprivation results from increased OGT and decreased O-GlcNAcase levels and that these changes affect cell metabolism, thus inactivating glycogen synthase. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|