The Lysosomal v-ATPase-Ragulator Complex Is a Common Activator for AMPK and mTORC1, Acting as a Switch between Catabolism and Anabolism
The Lysosomal v-ATPase-Ragulator Complex Is a Common Activator for AMPK and mTORC1, Acting as a Switch between Catabolism and Anabolism
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溶酶体 v-ATPase-Ragulator 复合物是 AMPK 和 mTORC1 的常见激活剂，充当分解代谢和合成代谢之间的开关
DOI：
10.1016/j.cmet.2014.06.014
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发表时间：
2014-09-02
期刊：
影响因子：
29
通讯作者：
Lin, Sheng-Cai
中科院分区：
文献类型：
--
作者：
Zhang, Chen-Song;Jiang, Bin;Lin, Sheng-Cai
AMPK和mTOR在管理代谢程序中发挥主要作用;然而，这两种反向调节激酶协调的机制仍不清楚。在这项研究中，我们发现，最令人惊讶的是，晚期内体/溶酶体蛋白复合物v-ATPase-Ragulator，激活mTORC 1所必需的，也是AMPK激活所必需的。我们还发现AMPK是晚期内体/溶酶体的驻留蛋白。在葡萄糖饥饿下，v-ATPase-Ragulator复合物可接近AXIN/LKB 1以激活AMPK。同时，Ragulator对RAG的鸟嘌呤核苷酸交换因子（GEF）活性被AXIN抑制，导致从内体解离和mTORC 1失活。因此，我们揭示了v-ATP酶-Ragulator复合物也是能量应激的起始传感器，同时通过形成v-ATP酶-Ragulator-轴蛋白/LKB 1-AMPK复合物作为LKB 1介导的AMPK激活的内体对接位点，从而提供了catalytic和analytic之间的开关。我们目前的研究还强调了晚期内体/溶酶体在控制代谢程序中的一般作用。
AMPK and mTOR play principal roles in governing metabolic programs; however, mechanisms underlying the coordination of the two inversely regulated kinases remain unclear. In this study we found, most surprisingly, that the late endosomal/lysosomal protein complex v-ATPase-Ragulator, essential for activation of mTORC1, is also required for AMPK activation. We also uncovered that AMPK is a residential protein of late endosome/lysosome. Under glucose starvation, the v-ATPase-Ragulator complex is accessible to AXIN/LKB1 for AMPK activation. Concurrently, the guanine nucleotide exchange factor (GEF) activity of Ragulator toward RAG is inhibited by AXIN, causing dissociation from endosome and inactivation of mTORC1. We have thus revealed that the v-ATPase-Ragulator complex is also an initiating sensor for energy stress and meanwhile serves as an endosomal docking site for LKB1-mediated AMPK activation by forming the v-ATPase-Ragulator-AXIN/LKB1-AMPK complex, thereby providing a switch between catabolism and anabolism. Our current study also emphasizes a general role of late endosome/lysosome in controlling metabolic programs.