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Cell Metab. 2014 Sep 2;20(3):526-40. doi: 10.1016/j.cmet.2014.06.014. Epub 2014 Jul 4.

The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism.

Author information

1
State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
2
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China.
3
Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China.
4
School of Life Sciences, Tsinghua University, Beijing 100101, China.
5
State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China. Electronic address: linsc@xmu.edu.cn.

Abstract

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.

PMID:
25002183
DOI:
10.1016/j.cmet.2014.06.014
[Indexed for MEDLINE]
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