Differential regulation of mTORC1 by leucine and glutamine

Themechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates environmental and intracellular signals to regulate cell growth. Amino acids stimulate mTORC1 activation at the lysosome in a manner thought to be dependent on the Rag small guanosine triphosphatases (GTPases), the Ragulator complex, and the vacuolar H⁺-adenosine triphosphatase (v-ATPase).We report that leucine and glutamine stimulate mTORC1 by Rag GTPase-dependent and -independent mechanisms, respectively. Glutamine promoted mTORC1 translocation to the lysosomein RagA and RagB knockout cells and required the v-ATPase but not the Ragulator. Furthermore,we identified the adenosine diphosphate ribosylation factor-1 GTPase to be required for mTORC1 activation and lysosomal localization by glutamine. Our results uncover a signaling cascade to mTORC1 activation independent of the RagGTPases and suggest that mTORC1 is differentially regulated by specific amino acids.