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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adaptor Proteins, Signal Transducing / 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*

Substances

  • Adaptor Proteins, Signal Transducing
  • Axin Protein
  • Multiprotein Complexes
  • late endosome-lysosome membrane adaptor p18, mouse
  • Stk11 protein, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Vacuolar Proton-Translocating ATPases
  • Glucose