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Science 334 (6056): 678-683

Copyright © 2011 by the American Association for the Advancement of Science

mTORC1 Senses Lysosomal Amino Acids Through an Inside-Out Mechanism That Requires the Vacuolar H+-ATPase

Roberto Zoncu,1,2,3,4 Liron Bar-Peled,1,2,3 Alejo Efeyan,1,2,3 Shuyu Wang,1,2,3 Yasemin Sancak,1,2,3 David M. Sabatini1,2,3,4,5,*

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.

1 Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
2 Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
3 David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
4 Broad Institute, Seven Cambridge Center, Cambridge, MA 02142, USA.
5 Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA.

* To whom correspondence should be addressed. E-mail: sabatini{at}wi.mit.edu

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