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

• Published in: Cell metabolism Vol. 20; no. 3; pp. 526 - 540
• Main Authors: Zhang, Chen-Song, Jiang, Bin, Li, Mengqi, Zhu, Mingjiang, Peng, Yongying, Zhang, Ya-Lin, Wu, Yu-Qing, Li, Terytty Yang, Liang, Yu, Lu, Zailian, Lian, Guili, Liu, Qing, Guo, Huiling, Yin, Zhenyu, Ye, Zhiyun, Han, Jiahuai, Wu, Jia-Wei, Yin, Huiyong, Lin, Shu-Yong, Lin, Sheng-Cai
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.09.2014
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; AMP-Activated Protein Kinases - metabolism; Animals; Axin Protein - metabolism; Cell Line; Endosomes - metabolism; Enzyme Activation; Glucose - metabolism; HEK293 Cells; Humans; Lysosomes - enzymology; Lysosomes - metabolism; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes - metabolism; Protein-Serine-Threonine Kinases - metabolism; Starvation; TOR Serine-Threonine Kinases - metabolism; Vacuolar Proton-Translocating ATPases - metabolism
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2014.06.014

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. [Display omitted] •Ragulator is essential for starvation-induced AMPK activation•LKB1-dependent activation of AMPK takes place on late endosome/lysosome•V-ATPase-Ragulator provides docking sites for AXIN/LKB1 endosomal translocation•V-ATPase-Ragulator is a switch between anabolism and catabolism AMPK and mTOR regulate cellular balance between catabolism and anabolism. Zhang et al. show that the endosomal v-ATPase-Ragulator complex, required for mTORC1 activation when nutrients are abundant, is also essential in LKB1-mediated AMPK activation in response to energy stress, thus acting as a dual energy sensor.