Editors' ChoiceCell Biology

Defining how amino acid deprivation inhibits mTORC1

Sci. Signal.  01 Dec 2015:
Vol. 8, Issue 405, pp. ec357
DOI: 10.1126/scisignal.aad9374

The mechanistic target of rapamycin complex 1 (mTORC1) and general control nonderepressible 2 (GCN2) regulate cellular responses to amino acid availability. In the presence of amino acids, mTORC1 is recruited to the surface of lysosomes, promotes protein translation and cell proliferation, and inhibits autophagy. The kinase GCN2 is activated by amino acid starvation, through dimerization and autophosphorylation that occurs when bound to uncharged tRNAs. GCN2 phosphorylates the eukaryotic initiation factor 2α (eIF2α), which inhibits the translation of most cellular mRNAs but stimulates translation of some mRNAs, including transcripts encoding the stress-responsive transcription factor ATF4. ATF4, in turn, stimulates the expression of genes that promote autophagy, amino acid uptake, and amino acid biosynthesis. Ye et al. found that prolonged leucine deprivation reduced mTORC1 activity and lysosomal localization in mouse embryonic fibroblasts (MEFs) in a manner that depended on GCN2. In MEFs and in two human cancer cell lines, leucine starvation caused ATF4 to stimulate the transcription of Sestrin2, which encodes a protein that blocks lysosomal localization of mTORC1. Inhibition of mTORC1 activity and lysosomal localization in leucine-starved MEFs required Sestrin2 and ATF4. Leucine or glutamine deprivation, but not endoplasmic reticulum stress (a process that also inhibits mTORC1 through a pathway involving ATF4 and Sestrin2), involved GCN2-mediated inhibition of mTORC1, indicating that GCN2 was specifically involved in the response to amino acid deprivation. Prolonged glutamine withdrawal caused most Sestrin2–/– MEFs and approximately half of GCN2–/– MEFs to undergo apoptosis, but inhibition of mTORC1 with rapamycin increased survival in both contexts. Thus, in addition to stimulating amino acid acquisition and autophagy, GCN2 also inhibits mTORC1 activity by preventing its translocation to lysosomes. These results also identify a mechanism whereby deprivation of a single amino acid—not only a general decrease in amino acid availability—can inhibit mTORC1 activity to promote cell survival.

J. Ye, W. Palm, M. Peng, B. King, T. Lindsten, M. O. Li, C. Koumenis, C. B. Thompson, GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2. Genes Dev. 29, 2331–2336 (2015). [PubMed]