The Lysosomal v-ATPase-Ragulator Complex Is a Common Activator for AMPK and mTORC1, Acting as a Switch between Catabolism and Anabolism

被引:409
作者
Zhang, Chen-Song [1 ]
Jiang, Bin [1 ]
Li, Mengqi [1 ]
Zhu, Mingjiang [2 ]
Peng, Yongying [1 ]
Zhang, Ya-Lin [1 ]
Wu, Yu-Qing [1 ]
Li, Terytty Yang [1 ]
Liang, Yu [1 ]
Lu, Zailian [1 ]
Lian, Guili [1 ]
Liu, Qing [1 ]
Guo, Huiling [3 ]
Yin, Zhenyu [3 ]
Ye, Zhiyun [1 ]
Han, Jiahuai [1 ]
Wu, Jia-Wei [4 ]
Yin, Huiyong [2 ]
Lin, Shu-Yong [1 ]
Lin, Sheng-Cai [1 ]
机构
[1] Xiamen Univ, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian, Peoples R China
[2] Chinese Acad Sci, SIBS, INS, Key Lab Food Safety Res, Shanghai 200031, Peoples R China
[3] Xiamen Univ, Zhongshan Hosp, Dept Hepatobiliary Surg, Xiamen 361004, Fujian, Peoples R China
[4] Tsinghua Univ, Sch Life Sci, Beijing 100101, Peoples R China
基金
中国国家自然科学基金;
关键词
TUMOR-SUPPRESSOR COMPLEX; PROTEIN-KINASE; RAG GTPASES; TUBEROUS SCLEROSIS; ALLOSTERIC ACTIVATION; GROWTH-CONTROL; PHOSPHORYLATION; MECHANISM; NUTRIENT; LKB1;
D O I
10.1016/j.cmet.2014.06.014
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:526 / 540
页数:15
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