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      The yeast H +-ATPase Pma1 promotes Rag/Gtr-dependent TORC1 activation in response to H +-coupled nutrient uptake

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          Abstract

          The yeast Target of Rapamycin Complex 1 (TORC1) plays a central role in controlling growth. How amino acids and other nutrients stimulate its activity via the Rag/Gtr GTPases remains poorly understood. We here report that the signal triggering Rag/Gtr-dependent TORC1 activation upon amino-acid uptake is the coupled H + influx catalyzed by amino-acid/H + symporters. H +-dependent uptake of other nutrients, ionophore-mediated H + diffusion, and inhibition of the vacuolar V-ATPase also activate TORC1. As the increase in cytosolic H + elicited by these processes stimulates the compensating H +-export activity of the plasma membrane H +-ATPase (Pma1), we have examined whether this major ATP-consuming enzyme might be involved in TORC1 control. We find that when the endogenous Pma1 is replaced with a plant H +-ATPase, H + influx or increase fails to activate TORC1. Our results show that H + influx coupled to nutrient uptake stimulates TORC1 activity and that Pma1 is a key actor in this mechanism.

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          Cells adapt their growth rate depending on the amount of nutrients available. The protein complex called TORC1 plays a central role in this. When nutrients are abundant, TORC1 is very active and stimulates the production of proteins and other molecules needed for the cell to grow. However, when nutrients such as amino acids become scarce, TORC1 reduces its activity and allows the cells to adapt to starvation. This TORC1-mediated control of the metabolism is crucial for the cell to survive, and faulty TORC1 proteins have been associated with several diseases including cancers.

          TORC1 was originally discovered in yeast, which provides a powerful model to study this control system. However, until now, it was not known how TORC1 is reactivated when amino acids are added to cells that have been starved of these molecules. Knowing the answer to this question would allow us to better understand how the availability of nutrients controls the activity of TORC1.

          Now, Saliba et al. have discovered that TORC1 is not reactivated by the amino acids themselves, but by protons, which are positively charged hydrogen ions that travel into the cell together with the amino acids. This influx of protons is the driving force behind the active transport of amino acids and other nutrients into the cell, and potentially serves as a general signal to activate TORC1 in response to the uptake of nutrients, especially when cells have been starved.

          Furthermore, the results showed that a specific enzyme in the cell membrane plays an essential role in activating TORC1. This enzyme pumps the protons out of the cell to compensate for their influx and to maintain the proton gradient in the membrane that drives the absorption of nutrients. When this enzyme was replaced with an equivalent plant enzyme, the proton-coupled nutrient uptake did not activate TORC1 in the yeast cells.

          These findings may help scientists who are interested in how TORC1 is regulated in organisms other than mammals, such as plants or fungi. A next step will be to find out how exactly the proton pump in the cell membrane helps to activate TORC1.

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          Most cited references 82

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          mTOR Signaling in Growth, Metabolism, and Disease.

          The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.
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            The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.

            The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins--a family of four related small guanosine triphosphatases (GTPases)--interact with mTORC1 in an amino acid-sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. A Rag mutant that is constitutively bound to guanosine triphosphate interacted strongly with mTORC1, and its expression within cells made the mTORC1 pathway resistant to amino acid deprivation. Conversely, expression of a guanosine diphosphate-bound Rag mutant prevented stimulation of mTORC1 by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb.
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              Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids.

              The mTORC1 kinase promotes growth in response to growth factors, energy levels, and amino acids, and its activity is often deregulated in disease. The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb. We show that amino acids induce the movement of mTORC1 to lysosomal membranes, where the Rag proteins reside. A complex encoded by the MAPKSP1, ROBLD3, and c11orf59 genes, which we term Ragulator, interacts with the Rag GTPases, recruits them to lysosomes, and is essential for mTORC1 activation. Constitutive targeting of mTORC1 to the lysosomal surface is sufficient to render the mTORC1 pathway amino acid insensitive and independent of Rag and Ragulator, but not Rheb, function. Thus, Rag-Ragulator-mediated translocation of mTORC1 to lysosomal membranes is the key event in amino acid signaling to mTORC1. Copyright 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                23 March 2018
                2018
                : 7
                Affiliations
                [1 ]deptMolecular Physiology of the Cell Université Libre de Bruxelles, Biopark GosseliesBelgium
                [2 ]Institut de Recherches Microbiologiques J.-M. Wiame BrusselsBelgium
                University of Basel Switzerland
                University of Basel Switzerland
                Author notes
                [†]

                These authors contributed equally to this work.

                Article
                31981
                10.7554/eLife.31981
                5915174
                29570051
                © 2018, Saliba et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Product
                Funding
                Funded by: Fonds National de La Recherche Scientifique;
                Award ID: 3.4.592.08.F
                Award Recipient :
                Funded by: Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture;
                Award ID: 21074048
                Award Recipient :
                Funded by: Fonds National de La Recherche Scientifique;
                Award ID: 22396499
                Award Recipient :
                Funded by: Fonds National de La Recherche Scientifique;
                Award ID: 30274494
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Cell Biology
                Custom metadata
                The H+ influx coupled to nutrient uptake and the plasma membrane H+-ATPase are central actors of the activation of target of rapamycin complex 1 (TORC1) in budding yeast Saccharomyces cerevisiae..

                Life sciences

                nutrient signaling, torc1, h+-atpase, membrane transport, yeast, s. cerevisiae

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