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mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase.

The mTOR complex 1 (mTORC1) protein kinase is a master growth regulator that is stimulated by amino acids. Amino acids activate the Rag guanosine triphosphatases (GTPases), which promote the translocation of mTORC1 to the lysosomal surface, the site of mTORC1 activation. We found that the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1. The v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome. In a cell-free system, ATP hydrolysis by the v-ATPase was necessary for amino acids to regulate the v-ATPase-Ragulator interaction and promote mTORC1 translocation. Results obtained in vitro and in human cells suggest that amino acid signaling begins within the lysosomal lumen. These results identify the v-ATPase as a component of the mTOR pathway and delineate a lysosome-associated machinery for amino acid sensing.

Pubmed ID: 22053050


  • Zoncu R
  • Bar-Peled L
  • Efeyan A
  • Wang S
  • Sancak Y
  • Sabatini DM


Science (New York, N.Y.)

Publication Data

November 4, 2011

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI47389
  • Agency: NCI NIH HHS, Id: CA103866
  • Agency: NCI NIH HHS, Id: R01 CA103866
  • Agency: NCI NIH HHS, Id: R01 CA103866-07
  • Agency: NCI NIH HHS, Id: R01 CA103866-08
  • Agency: NIAID NIH HHS, Id: R37 AI047389
  • Agency: NIAID NIH HHS, Id: R37 AI047389-11
  • Agency: NIAID NIH HHS, Id: R37 AI047389-12
  • Agency: NIAID NIH HHS, Id: R37 AI047389-13
  • Agency: NIGMS NIH HHS, Id: T32 GM007753
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Amino Acids
  • Animals
  • Cell Line
  • Drosophila
  • GTP Phosphohydrolases
  • Humans
  • Lysosomes
  • Multiprotein Complexes
  • Proteins
  • RNA Interference
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Vacuolar Proton-Translocating ATPases