Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1
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Sabatini_Metabolism lysosomal.pdf
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Author(s)
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.
Date Issued
January 2015
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
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.
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Author's final manuscript
Abstract
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.
MIT Department
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
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DOI of Published Version
https://doi.org/10.1126/science.1257132
