AMPK-mediated phosphorylation enhances the auto-inhibition of TBC1D17 to promote Rab5-dependent glucose uptake
| Autor: | Yi Ting Zhou, Lin Jing Shi, Chen-Yao Ni, Xi Sheng Rao, Xiu Kui Gao, Peng Lin, Jian Feng Wang, Cong Yi, Zhuo Xian Meng, Li Ling Zheng, Jinling Liu, Yingke Xu, Yin Pu Shi, Xiao Xia Cong, Ming Jie He |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine GTPase-activating protein Glucose uptake AMP-Activated Protein Kinases Transfection environment and public health Article Mice 03 medical and health sciences 0302 clinical medicine Animals Humans Glucose homeostasis Small GTPase Amino Acid Sequence Phosphorylation Protein kinase A Molecular Biology rab5 GTP-Binding Proteins biology Chemistry GTPase-Activating Proteins AMPK Cell Biology Cell biology enzymes and coenzymes (carbohydrates) Glucose 030104 developmental biology Diabetes Mellitus Type 2 030220 oncology & carcinogenesis biology.protein Insulin Resistance GLUT4 |
| Zdroj: | Cell Death Differ |
| ISSN: | 1476-5403 1350-9047 |
| Popis: | Dysregulation of glucose homeostasis contributes to insulin resistance and type 2 diabetes. Whilst exercise stimulated activation of AMP-activated protein kinase (AMPK), an important energy sensor, has been highlighted for its potential to promote insulin-stimulated glucose uptake, the underlying mechanisms for this remain largely unknown. Here we found that AMPK positively regulates the activation of Rab5, a small GTPase which is involved in regulating Glut4 translocation, in both myoblasts and skeletal muscles. We further verified that TBC1D17, identified as a potential interacting partner of Rab5 in our recent study, is a novel GTPase activating protein (GAP) of Rab5. TBC1D17-Rab5 axis regulates transport of Glut1, Glut4, and transferrin receptor. TBC1D17 interacts with Rab5 or AMPK via its TBC domain or N-terminal 1-306 region (N-Ter), respectively. Moreover, AMPK phosphorylates the Ser 168 residue of TBC1D17 which matches the predicted AMPK consensus motif. N-Ter of TBC1D17 acts as an inhibitory region by directly interacting with the TBC domain. Ser168 phosphorylation promotes intra-molecular interaction and therefore enhances the auto-inhibition of TBC1D17. Our findings reveal that TBC1D17 acts as a molecular bridge that links AMPK and Rab5 and delineate a previously unappreciated mechanism by which the activation of TBC/RabGAP is regulated. |
| Databáze: | OpenAIRE |
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