Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1
The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase–dependent fashion, the translocation of mTORC1 to the lysosomal surface...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science (AAAS)
2015
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| Online Access: | http://hdl.handle.net/1721.1/96751 https://orcid.org/0000-0003-4642-3706 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0002-4227-5163 https://orcid.org/0000-0001-6366-7986 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0001-9388-1633 |
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| author | Plovanich, M. E. Straub, C. Sabatini, B. L. Tsun, Zhi-Yang Wang, Shuyu Wolfson, Rachel Laura Shen, Kuang Wyant, Gregory Andrew Yuan, Elizabeth D. Jones, Tony D. Chantranupong, Lynne Comb, William C. Wang, Tim Bar-Peled, Liron Zoncu, Roberto Kim, Choah Park, Jiwon Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Plovanich, M. E. Straub, C. Sabatini, B. L. Tsun, Zhi-Yang Wang, Shuyu Wolfson, Rachel Laura Shen, Kuang Wyant, Gregory Andrew Yuan, Elizabeth D. Jones, Tony D. Chantranupong, Lynne Comb, William C. Wang, Tim Bar-Peled, Liron Zoncu, Roberto Kim, Choah Park, Jiwon Sabatini, David |
| author_sort | Plovanich, M. E. |
| collection | MIT |
| description | The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase–dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag guanosine triphosphatases (GTPases) and Ragulator in an amino acid–sensitive fashion. SLC38A9 transports arginine with a high Michaelis constant, and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is an excellent candidate for being an arginine sensor for the mTORC1 pathway. |
| first_indexed | 2024-09-23T08:39:57Z |
| format | Article |
| id | mit-1721.1/96751 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:39:57Z |
| publishDate | 2015 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/967512022-09-23T13:39:27Z Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1 Plovanich, M. E. Straub, C. Sabatini, B. L. Tsun, Zhi-Yang Wang, Shuyu Wolfson, Rachel Laura Shen, Kuang Wyant, Gregory Andrew Yuan, Elizabeth D. Jones, Tony D. Chantranupong, Lynne Comb, William C. Wang, Tim Bar-Peled, Liron Zoncu, Roberto Kim, Choah Park, Jiwon Sabatini, David Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Tsun, Zhi-Yang Wang, Shuyu Wolfson, Rachel Laura Shen, Kuang Wyant, Gregory Andrew Yuan, Elizabeth D. Jones, Tony D. Chantranupong, Lynne Comb, William C. Wang, Tim Bar-Peled, Liron Zoncu, Roberto Kim, Choah Park, Jiwon Sabatini, David M. The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase–dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag guanosine triphosphatases (GTPases) and Ragulator in an amino acid–sensitive fashion. SLC38A9 transports arginine with a high Michaelis constant, and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is an excellent candidate for being an arginine sensor for the mTORC1 pathway. National Institutes of Health (U.S.) (Grant R01 CA103866) National Institutes of Health (U.S.) (Grant AI47389) United States. Dept. of Defense (W81XWH-07-0448) National Institutes of Health (U.S.) (Fellowship F30CA180754) National Institutes of Health (U.S.) (Fellowship T32 GM007753) National Institutes of Health (U.S.) (Fellowship F31 AG044064) National Institutes of Health (U.S.) (Fellowship F31CA180271) United States. Dept. of Defense (National Defense Science and Engineering Graduate Fellowship) National Science Foundation (U.S.). Graduate Research Fellowship Program American Cancer Society (Ellison Medical Foundation. Postdoctoral Fellowship PF-13-356-01-TBE) Howard Hughes Medical Institute 2015-04-23T18:19:44Z 2015-04-23T18:19:44Z 2015-01 2014-06 Article http://purl.org/eprint/type/JournalArticle 0036-8075 1095-9203 http://hdl.handle.net/1721.1/96751 Wang, S., Z.-Y. Tsun, R. L. Wolfson, K. Shen, G. A. Wyant, M. E. Plovanich, E. D. Yuan, et al. “Lysosomal Amino Acid Transporter SLC38A9 Signals Arginine Sufficiency to mTORC1.” Science 347, no. 6218 (January 7, 2015): 188–194. https://orcid.org/0000-0003-4642-3706 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0002-4227-5163 https://orcid.org/0000-0001-6366-7986 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0001-9388-1633 en_US http://dx.doi.org/10.1126/science.1257132 Science Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Plovanich, M. E. Straub, C. Sabatini, B. L. Tsun, Zhi-Yang Wang, Shuyu Wolfson, Rachel Laura Shen, Kuang Wyant, Gregory Andrew Yuan, Elizabeth D. Jones, Tony D. Chantranupong, Lynne Comb, William C. Wang, Tim Bar-Peled, Liron Zoncu, Roberto Kim, Choah Park, Jiwon Sabatini, David Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1 |
| title | Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1 |
| title_full | Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1 |
| title_fullStr | Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1 |
| title_full_unstemmed | Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1 |
| title_short | Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1 |
| title_sort | lysosomal amino acid transporter slc38a9 signals arginine sufficiency to mtorc1 |
| url | http://hdl.handle.net/1721.1/96751 https://orcid.org/0000-0003-4642-3706 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0002-4227-5163 https://orcid.org/0000-0001-6366-7986 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0001-9388-1633 |
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