mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the Vacuolar H+-ATPase

By Roberto Zoncu, L. Bar-Peled, A. Efeyan, Shuyu Wang, Y. Sancak, David M. Sabatini. Science, 2011

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Cellular sensing of amino acids occurs at the lysosome and is mediated by the vacuolar proton pump. 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.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3e26b18ccae4d1ef49aa5e00116132287c3e435e

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Citations in the corpus

Regulation of mTORC1 by amino acids (2014, neutral): “The use of a cell-free reconstitution assay suggested that the amino acid signal initiates from within the lysosomal lumen (39).”
Phosphoinositides: tiny lipids with giant impact on cell regulation. (2013, background): “The amino acid sensing, however, is mediated by a different pathway that involves the Rag GTPases (785, 1336) and one that requires translocation of the mTORC1 complex to the surface of the lysosomes (1335, 1829).”
The CASTOR proteins are arginine sensors for the mTORC1 pathway (2016, neutral): “While Sestrin2 interacts with GATOR2 to inhibit mTORC1 signaling in the absence of leucine, SLC38A9 forms a supercomplex with Ragulator and is necessary for transmitting arginine, but not leucine, sufficiency to mTORC1 (Chantranupong et al., 2014; Jung et al., 2015; Lynch et al., 2000; Rebsamen et a”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, neutral): “AMPK inhibits MTOR by phosphorylating and activating TSC2.(487) Therefore, AMPK is involved in processes that synergize to activate autophagy, by directly activating ULK1, and indirectly impairing MTOR-dependent inhibition of ULK1.”
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I (2020, neutral): “For lysosome immunoprecipitation experiments, HPDE and human PDAC cell lines stably expressing TMRHA were ruptured and intact lysosomes from 1–2 mg of total protein per sample was immunoprecipitated using HA-conjugated Dynabeads as previously described 45,46 .”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “GATOR1 consists of DEPDC5, Nprl2, and Nprl3 and inhibits mTORC1 signaling by acting as a GAP for RagA/B.”
Nutrient sensing and signaling in the yeast Saccharomyces cerevisiae (2014, background): “…regulation by interaction with other lysosome/vacuole membrane-localized complexes has led to an emergent model by which TORC1 would respond to changes in intracellular amino acid availability determined by v-ATPase-dependent export of vacuolar amino acids to the cytosol (Zoncu et al., 2011).”
A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB (2012, background): “Consistent with this idea, chloroquine or SalA inhibited mTORC1 activity as measured by level of p-P70S6K, a known mTORC1 substrate (Figure 2A; Zoncu et al , 2011a).”
The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction. (2012, neutral): “In turn, mTOR reactivation depends on the completion of autolysosomal substrate digestion, and sufficient levels of luminal amino acids (Zoncu et al., 2011).”
AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control. (2020, background): “257 p18/LAMTOR1 is a key component of the Ragulator complex, which (as will be discussed later) 258 plays a central role in the activation of mTORC1 via interaction with the vacuolar ATPase (v-259 ATPase) (Bar-Peled et al., 2012; Sancak et al., 2010; Zoncu et al., 2011).”