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mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux

Sensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We report here an additional important step in the activation of mTORC1, which regulates the efflux of...

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Autores principales: Beaumatin, Florian, O’Prey, Jim, Barthet, Valentin J.A., Zunino, Barbara, Parvy, Jean-Philippe, Bachmann, Alexis Maximilien, O’Prey, Margaret, Kania, Elżbieta, Gonzalez, Pablo Sierra, Macintosh, Robin, Lao, Laurence Y., Nixon, Colin, Lopez, Jonathan, Long, Jaclyn S., Tait, Stephen W.G., Ryan, Kevin M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892261/
https://www.ncbi.nlm.nih.gov/pubmed/31492633
http://dx.doi.org/10.1016/j.molcel.2019.07.021
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author Beaumatin, Florian
O’Prey, Jim
Barthet, Valentin J.A.
Zunino, Barbara
Parvy, Jean-Philippe
Bachmann, Alexis Maximilien
O’Prey, Margaret
Kania, Elżbieta
Gonzalez, Pablo Sierra
Macintosh, Robin
Lao, Laurence Y.
Nixon, Colin
Lopez, Jonathan
Long, Jaclyn S.
Tait, Stephen W.G.
Ryan, Kevin M.
author_facet Beaumatin, Florian
O’Prey, Jim
Barthet, Valentin J.A.
Zunino, Barbara
Parvy, Jean-Philippe
Bachmann, Alexis Maximilien
O’Prey, Margaret
Kania, Elżbieta
Gonzalez, Pablo Sierra
Macintosh, Robin
Lao, Laurence Y.
Nixon, Colin
Lopez, Jonathan
Long, Jaclyn S.
Tait, Stephen W.G.
Ryan, Kevin M.
author_sort Beaumatin, Florian
collection PubMed
description Sensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We report here an additional important step in the activation of mTORC1, which regulates the efflux of amino acids from lysosomes into the cytoplasm. This process requires DRAM-1, which binds the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, directing them to lysosomes and permitting efficient mTORC1 activation. Consequently, we show that loss of DRAM-1 also impacts pathways regulated by mTORC1, including insulin signaling, glycemic balance, and adipocyte differentiation. Interestingly, although DRAM-1 can promote autophagy, this effect on mTORC1 is autophagy independent, and autophagy only becomes important for mTORC1 activation when DRAM-1 is deleted. These findings provide important insights into mTORC1 activation and highlight the importance of DRAM-1 in growth control, metabolic homeostasis, and differentiation.
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spelling pubmed-68922612019-12-16 mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux Beaumatin, Florian O’Prey, Jim Barthet, Valentin J.A. Zunino, Barbara Parvy, Jean-Philippe Bachmann, Alexis Maximilien O’Prey, Margaret Kania, Elżbieta Gonzalez, Pablo Sierra Macintosh, Robin Lao, Laurence Y. Nixon, Colin Lopez, Jonathan Long, Jaclyn S. Tait, Stephen W.G. Ryan, Kevin M. Mol Cell Article Sensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We report here an additional important step in the activation of mTORC1, which regulates the efflux of amino acids from lysosomes into the cytoplasm. This process requires DRAM-1, which binds the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, directing them to lysosomes and permitting efficient mTORC1 activation. Consequently, we show that loss of DRAM-1 also impacts pathways regulated by mTORC1, including insulin signaling, glycemic balance, and adipocyte differentiation. Interestingly, although DRAM-1 can promote autophagy, this effect on mTORC1 is autophagy independent, and autophagy only becomes important for mTORC1 activation when DRAM-1 is deleted. These findings provide important insights into mTORC1 activation and highlight the importance of DRAM-1 in growth control, metabolic homeostasis, and differentiation. Cell Press 2019-10-03 /pmc/articles/PMC6892261/ /pubmed/31492633 http://dx.doi.org/10.1016/j.molcel.2019.07.021 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Beaumatin, Florian
O’Prey, Jim
Barthet, Valentin J.A.
Zunino, Barbara
Parvy, Jean-Philippe
Bachmann, Alexis Maximilien
O’Prey, Margaret
Kania, Elżbieta
Gonzalez, Pablo Sierra
Macintosh, Robin
Lao, Laurence Y.
Nixon, Colin
Lopez, Jonathan
Long, Jaclyn S.
Tait, Stephen W.G.
Ryan, Kevin M.
mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux
title mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux
title_full mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux
title_fullStr mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux
title_full_unstemmed mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux
title_short mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux
title_sort mtorc1 activation requires dram-1 by facilitating lysosomal amino acid efflux
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892261/
https://www.ncbi.nlm.nih.gov/pubmed/31492633
http://dx.doi.org/10.1016/j.molcel.2019.07.021
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