Acetylation of TUG Protein Promotes the Accumulation of GLUT4 Glucose Transporters in an Insulin-responsive Intracellular Compartment
| Autor: | Estifanos N. Habtemichael, Leah McNally, Jonathan P. Belman, Abel R. Alcázar-Román, Don T. Li, Gerald I. Shulman, Rachel R. Bian, Jonathan S. Bogan, Michael J. Jurczak |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Cytoplasm Endosome Glucose uptake medicine.medical_treatment Blotting Western Real-Time Polymerase Chain Reaction SIRT2 Biochemistry Mice Sirtuin 2 3T3-L1 Cells Adipocytes medicine Animals Humans Hypoglycemic Agents Immunoprecipitation Insulin Cystinyl Aminopeptidase RNA Messenger Molecular Biology Cells Cultured Mice Knockout Glucose Transporter Type 4 biology Reverse Transcriptase Polymerase Chain Reaction Cell Membrane Intracellular Signaling Peptides and Proteins Glucose transporter Acetylation Cell Biology Flow Cytometry Mice Inbred C57BL Protein Transport Glucose Metabolism biology.protein Carrier Proteins human activities hormones hormone substitutes and hormone antagonists GLUT4 Intracellular |
| Zdroj: | Journal of Biological Chemistry. 290:4447-4463 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m114.603977 |
| Popis: | Insulin causes the exocytic translocation of GLUT4 glucose transporters to stimulate glucose uptake in fat and muscle. Previous results support a model in which TUG traps GLUT4 in intracellular, insulin-responsive vesicles termed GLUT4 storage vesicles (GSVs). Insulin triggers TUG cleavage to release the GSVs; GLUT4 then recycles through endosomes during ongoing insulin exposure. The TUG C terminus binds a GSV anchoring site comprising Golgin-160 and possibly other proteins. Here, we report that the TUG C terminus is acetylated. The TUG C-terminal peptide bound the Golgin-160-associated protein, ACBD3 (acyl-CoA-binding domain-containing 3), and acetylation reduced binding of TUG to ACBD3 but not to Golgin-160. Mutation of the acetylated residues impaired insulin-responsive GLUT4 trafficking in 3T3-L1 adipocytes. ACBD3 overexpression enhanced the translocation of GSV cargos, GLUT4 and insulin-regulated aminopeptidase (IRAP), and ACBD3 was required for intracellular retention of these cargos in unstimulated cells. Sirtuin 2 (SIRT2), a NAD(+)-dependent deacetylase, bound TUG and deacetylated the TUG peptide. SIRT2 overexpression reduced TUG acetylation and redistributed GLUT4 and IRAP to the plasma membrane in 3T3-L1 adipocytes. Mutation of the acetylated residues in TUG abrogated these effects. In mice, SIRT2 deletion increased TUG acetylation and proteolytic processing. During glucose tolerance tests, glucose disposal was enhanced in SIRT2 knock-out mice, compared with wild type controls, without any effect on insulin concentrations. Together, these data support a model in which TUG acetylation modulates its interaction with Golgi matrix proteins and is regulated by SIRT2. Moreover, acetylation of TUG enhances its function to trap GSVs within unstimulated cells and enhances insulin-stimulated glucose uptake. |
| Databáze: | OpenAIRE |
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