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.

葡萄糖稳态失调导致胰岛素抵抗和 2 型糖尿病。虽然运动刺激了 AMP 活化蛋白激酶 (AMPK) 的激活，一种重要的能量传感器，因其促进胰岛素刺激的葡萄糖摄取的潜力而受到强调，但其潜在机制在很大程度上仍然未知。在这里，我们发现 AMPK 积极调节 Rab5 的激活，Rab5 是一种小 GTP 酶，在成肌细胞和骨骼肌中参与调节 Glut4 易位。我们进一步证实，在我们最近的研究中被确定为 Rab5 潜在相互作用伙伴的 TBC1D17 是 Rab5 的一种新型 GTP 酶激活蛋白 (GAP)。TBC1D17-Rab5 轴调节 Glut1、Glut4 和转铁蛋白受体的转运。TBC1D17 通过其 TBC 结构域或 N 末端 1-306 区域（N-Ter）与 Rab5 或 AMPK 相互作用，分别。此外，AMPK 磷酸化与预测的 AMPK 共有基序匹配的 TBC1D17 的 Ser 168 残基。TBC1D17 的 N-Ter 通过与 TBC 结构域直接相互作用充当抑制区域。Ser168 磷酸化促进分子内相互作用，因此增强 TBC1D17 的自身抑制。我们的研究结果表明，TBC1D17 充当连接 AMPK 和 Rab5 的分子桥，并描绘了一种以前未被重视的机制，通过该机制调节 TBC/RabGAP 的激活。