期刊
CELL
卷 171, 期 3, 页码 642-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2017.09.046
关键词
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资金
- NIH [R01 CA103866, R01 CA129105, R37 AI47389, T32 GM007753, F30 CA189333, F32CA210421]
- Department of Defense [W81XWH-15-1-0230, W81XWH-15-1-0337]
- EMBO [ALTF-2014-1]
- National Defense Science & Engineering Graduate Fellowship (NDSEG) Program
- Lustgarten Foundation
- SU2C
- NCI [R01 CA168653, P30CA1405141]
- Howard Hughes Medical Institute (HHMI)
- Navitor Pharmaceuticals
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.
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