Metabolism. Differential regulation of mTORC1 by leucine and glutamine.
Bottom Line: 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).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 Rag GTPases and suggest that mTORC1 is differentially regulated by specific amino acids.
Affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.Show MeSH
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Mentions: The lysosome is essential in the amino acidsensing pathway to mTORC1 and is thought to be a platform for optimal mTORC1 activation that integrates effects of growth factors, such as insulin, through Rheb and those of amino acids through the Rags (19). Because Gln can activate mTORC1 in the absence of RagA and RagB (Fig. 1, C and E, fig. S7, and fig. S9F), we investigated whether lysosomal localization of mTORC1 was required for Gln-induced activation of mTORC1 in cells lacking RagA and RagB. In control cells, mTOR translocated to lysosomal membranes identified by the presence of the marker protein lysosome-associated membrane protein 2 (LAMP2) as early as 50 min and remained at the lysosome 150 min after amino acid stimulation (fig. S10A) (4, 11). In contrast, mTOR did not localize to lysosomal membranes in RagA/B KO cells after 50 min of amino acid stimulation (fig. S10B). However, by 150 min, we observed lysosomal localization of mTOR in a subset of cells that also showed activation of mTORC1 (Fig. 2A and fig. S10B). Gln, but not Leu, induced lysosomal localization of mTOR in RagA/B KO MEFs (Fig. 2, B and C). Furthermore, synergistic activation of mTOR by amino acids and insulin was observed in RagA/B KO cells (fig. S11). Thus, Gln appears to induce mTORC1 activation through translocation to the lysosome in a manner independent of RagA and RagB.
Affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.