AMPK-mediated phosphorylation enhances the auto-inhibition of TBC1D17 to promote Rab5-dependent glucose uptake
AMPK-mediated phosphorylation enhances the auto-inhibition of TBC1D17 to promote Rab5-dependent glucose uptake
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AMPK 介导的磷酸化增强 TBC1D17 的自身抑制，促进 Rab5 依赖性葡萄糖摄取
DOI：
10.1038/s41418-021-00809-9
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发表时间：
2021-05-27
影响因子：
12.4
通讯作者：
Zhou, Yi Ting
中科院分区：
文献类型：
--
作者：
Rao, Xi Sheng;Cong, Xiao Xia;Zhou, Yi Ting
葡萄糖稳态失调导致胰岛素抵抗和2型糖尿病。虽然运动刺激的AMP活化蛋白激酶（AMPK），一种重要的能量传感器，已被强调其促进胰岛素刺激的葡萄糖摄取的潜力，这在很大程度上仍然是未知的潜在机制。我们发现AMPK在成肌细胞和骨骼肌中都能积极调节Rab 5的激活，Rab 5是一种参与调节Glut 4转位的小GT3。我们进一步证实了TBC 1D 17是Rab 5的一个新的GT3激活蛋白（GAP），TBC 1D 17是Rab 5的一个潜在的相互作用伙伴。TBC 1D 17-Rab 5轴调节Glut 1、Glut 4和转铁蛋白受体的转运。TBC 1D 17分别通过其TBC结构域或N-末端1-306区（N-Ter）与Rab 5或AMPK相互作用。此外，AMPK磷酸化TBC 1D 17的Ser 168残基，其匹配预测的AMPK共有基序。TBC 1D 17的N-Ter通过与TBC结构域直接相互作用而充当抑制区域。Ser 168磷酸化促进分子内相互作用，因此增强TBC 1D 17的自抑制。我们的研究结果表明，TBC 1D 17作为一个分子桥梁，连接AMPK和Rab 5，并描绘了一个以前不受重视的机制，TBC/RabGAP的激活进行调节。
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.