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Review
. 2012 Sep;18(9):524-33.
doi: 10.1016/j.molmed.2012.05.007. Epub 2012 Jun 28.

Amino acids and mTORC1: from lysosomes to disease

Alejo Efeyan  1 , Roberto Zoncu, David M Sabatini
Affiliations
Review

Amino acids and mTORC1: from lysosomes to disease

Alejo Efeyan et al. Trends Mol Med. 2012 Sep.

Abstract

The mechanistic target of rapamycin (mTOR) kinase controls growth and metabolism, and its deregulation underlies the pathogenesis of many diseases, including cancer, neurodegeneration, and diabetes. mTOR complex 1 (mTORC1) integrates signals arising from nutrients, energy, and growth factors, but how exactly these signals are propagated await to be fully understood. Recent findings have placed the lysosome, a key mediator of cellular catabolism, at the core of mTORC1 regulation by amino acids. A multiprotein complex that includes the Rag GTPases, Ragulator, and the v-ATPase forms an amino acid-sensing machinery on the lysosomal surface that affects the decision between cell growth and catabolism at multiple levels. The involvement of a catabolic organelle in growth signaling may have important implications for our understanding of mTORC1-related pathologies.

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Figures

Figure 1
Figure 1
(a) Inputs and outputs of mechanistic target of rapamycin complex 1 (mTORC1) signaling. mTORC1 is formed by mTOR (target of rapamycin), raptor (regulatory associated protein of mTOR), GβL (mTOR associated protein LST8 homolog), and Deptor (DEP domain containing mTOR-interacting protein). mTORC1 integrates positive growth signals arising from amino acids and growth factors with inhibitory signals from hypoxia, low energy, and DNA damage. Upon activation, mTORC1 promotes several cellular anabolic processes, such as mRNA translation and ribosome biogenesis, lipid synthesis, whereas it blocks autophagy and other catabolic processes. mTORC1 activation also unleashes a negative feedback loop to the insulin receptor, which tends to dampen insulin/PI3K (phosphatidylinositol 3-kinase) signaling with profound physiological consequences. (b) mTORC1 and the lysosomal surface. Amino acids regulate the recruitment of mTORC1 to the lysosomal surface, where mTORC1 is activated. Under low amino acids (left) the v-ATPase (vacuolar H+-ATPase)–Ragulator (LAMTOR1–3)–Rag GTPase complex is in the inactive conformation and is unable to bind to mTORC1, resulting in its cytoplasmic localization. Amino acids (right), acting at least in part via a lysosomal ‘inside-out’ mechanism, signal to the v-ATPase–Ragulator complex and through them to the Rag GTPases, which switch their nucleotide loading and become activated. In turn, active Rag GTPases recruit mTORC1 to the lysosomal surface, where the small GTPase Rheb (Ras homolog enriched in brain) turns on the kinase activity of mTORC1. Active mTORC1 phosphorylates several targets, including S6K, 4E-BP1, the autophagy regulator ULK1 and the transcription factor TFEB. Phosphorylated S6K and 4E-BP1 favor protein synthesis; phosphorylation of ULK1 blocks autophagosome formation, whereas phosphorylation of TFEB prevents it from entering the nucleus and activating a catabolic transcriptional program.
Figure 2
Figure 2
Involvement of the target of rapamycin (mTOR) pathway in human disease syndromes. Germline mutations that affect target of rapamycin complex 1 (mTORC1) activity are found in syndromes associated with deregulated cell growth. Tuberous sclerosis, Von Hippel–Lindau disease (VHL), and Peutz–Jeghers syndrome directly affect mTORC1 activation without impacting PI3K (phosphatidylinositol 3-kinase)-Akt, whereas neurofibromatosis and the Cowden, Proteus, and Bannayan–Riley–Ruvalcaba syndromes involve PI3K-Akt dysregulation, indirectly leading to hyperactivation of mTORC1 and also affecting other downstream effectors. Remarkably, a rare syndrome associated with an almost complete loss of function of the Ragulator component LAMTOR2/p14 is the only known syndrome that affects amino acid-dependent activation of mTORC1, and the only syndrome that leads to mTORC1 hypoactivity.
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