title: mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase.
abstract: 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.
authors: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors: Roberto
authors: R
authors: Zoncu
authors: Liron
authors: L
authors: Bar-Peled
authors: Alejo
authors: A
authors: Efeyan
authors: Shuyu
authors: S
authors: Wang
authors: Yasemin
authors: Y
authors: Sancak
authors: David M
authors: DM
authors: Sabatini
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004330:Drosophila; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D046912:Multiprotein Complexes; D011506:Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020558:GTP Phosphohydrolases; D025262:Vacuolar Proton-Translocating ATPases