mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient
The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor...
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Elsevier
2018
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| Online Access: | http://hdl.handle.net/1721.1/118941 https://orcid.org/0000-0003-4642-3706 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0002-8206-8003 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0002-1446-7256 |
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| author | Freinkman, Elizaveta Wyant, Gregory Andrew Abu-Remaileh, Monther Wolfson, Rachel Laura Chen, Walter W. Danai, Laura V Vander Heiden, Matthew G. Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Freinkman, Elizaveta Wyant, Gregory Andrew Abu-Remaileh, Monther Wolfson, Rachel Laura Chen, Walter W. Danai, Laura V Vander Heiden, Matthew G. Sabatini, David |
| author_sort | Freinkman, Elizaveta |
| collection | MIT |
| description | The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins. SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1. Pancreatic cancer cells, which use macropinocytosed protein as a nutrient source, require SLC38A9 to form tumors. Thus, through SLC38A9, arginine serves as a lysosomal messenger that couples mTORC1 activation to the release from lysosomes of the essential amino acids needed to drive cell growth. SLC38A9 is an arginine-regulated transporter of major amino acids, including leucine, providing insights into the regulation of the mTORC pathway and its nutrient-sensing function. Keywords: amino acid sensing; nutrient sensing; mTOR; lysosome; micropinocytosis; autophagy |
| first_indexed | 2024-09-23T08:00:23Z |
| format | Article |
| id | mit-1721.1/118941 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T08:00:23Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1189412022-09-30T01:38:54Z mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient Freinkman, Elizaveta Wyant, Gregory Andrew Abu-Remaileh, Monther Wolfson, Rachel Laura Chen, Walter W. Danai, Laura V Vander Heiden, Matthew G. Sabatini, David Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Wyant, Gregory Andrew Abu-Remaileh, Monther Wolfson, Rachel Laura Chen, Walter W. Danai, Laura V Vander Heiden, Matthew G. Sabatini, David The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins. SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1. Pancreatic cancer cells, which use macropinocytosed protein as a nutrient source, require SLC38A9 to form tumors. Thus, through SLC38A9, arginine serves as a lysosomal messenger that couples mTORC1 activation to the release from lysosomes of the essential amino acids needed to drive cell growth. SLC38A9 is an arginine-regulated transporter of major amino acids, including leucine, providing insights into the regulation of the mTORC pathway and its nutrient-sensing function. Keywords: amino acid sensing; nutrient sensing; mTOR; lysosome; micropinocytosis; autophagy National Institutes of Health (U.S.) (Grant R01CA103866) National Institutes of Health (U.S.) (Grant R01 CA129105) National Institutes of Health (U.S.) (Grant R37AI47389) United States. Department of Defense (Grant W81XWH-15-1-0230) National Institutes of Health (U.S.) (Grant T32GM007753) National Institutes of Health (U.S.) (Grant F30-CA189333) National Institutes of Health (U.S.) (Grant F32CA210421) National Cancer Institute (U.S.) (Grant R01CA168653) National Cancer Institute (U.S.) (Grant P30CA1405141) 2018-11-07T16:47:17Z 2018-11-07T16:47:17Z 2017-10 2017-07 2018-11-06T14:01:25Z Article http://purl.org/eprint/type/JournalArticle 0092-8674 1097-4172 http://hdl.handle.net/1721.1/118941 Wyant, Gregory A. et al. “mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient.” Cell 171, 3 (October 2017): 642–654 © 2017 Elsevier Inc https://orcid.org/0000-0003-4642-3706 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0002-8206-8003 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0002-1446-7256 http://dx.doi.org/10.1016/J.CELL.2017.09.046 Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Freinkman, Elizaveta Wyant, Gregory Andrew Abu-Remaileh, Monther Wolfson, Rachel Laura Chen, Walter W. Danai, Laura V Vander Heiden, Matthew G. Sabatini, David mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient |
| title | mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient |
| title_full | mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient |
| title_fullStr | mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient |
| title_full_unstemmed | mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient |
| title_short | mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient |
| title_sort | mtorc1 activator slc38a9 is required to efflux essential amino acids from lysosomes and use protein as a nutrient |
| url | http://hdl.handle.net/1721.1/118941 https://orcid.org/0000-0003-4642-3706 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0002-8206-8003 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0002-1446-7256 |
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