title: The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism.
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.
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Chen-Song
authors.initials: CS
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Jiang
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Mengqi
authors.initials: M
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Zhu
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Yongying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Ya-Lin
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Wu
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Terytty Yang
authors.initials: TY
authors.lastname: Li
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liang
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Zailian
authors.initials: Z
authors.lastname: Lu
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Guili
authors.initials: G
authors.lastname: Lian
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yin
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Ye
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100101, China.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Huiyong
authors.initials: H
authors.lastname: Yin
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Shu-Yong
authors.initials: SY
authors.lastname: Lin
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361102, China. Electronic address: linsc@xmu.edu.cn.
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D060466:Axin Protein / Q000378:metabolism; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013217:Starvation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D046912:Multiprotein Complexes; C571152:late endosome-lysosome membrane adaptor p18, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D025262:Vacuolar Proton-Translocating ATPases; D005947:Glucose