mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient

Gregory A Wyant; Monther Abu-Remaileh; Rachel L Wolfson; Walter W Chen; Elizaveta Freinkman; Laura V Danai; Matthew G Vander Heiden; David M Sabatini

doi:10.1016/j.cell.2017.09.046

mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient

Cell. 2017 Oct 19;171(3):642-654.e12. doi: 10.1016/j.cell.2017.09.046.

Authors

Gregory A Wyant¹, Monther Abu-Remaileh¹, Rachel L Wolfson², Walter W Chen², Elizaveta Freinkman³, Laura V Danai⁴, Matthew G Vander Heiden⁵, David M Sabatini⁶

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.
² Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA; Harvard Medical School M.D.-Ph.D. Program, Daniel C. Tosteson Medical Education Center, 260 Longwood Avenue, Boston, MA 02115, USA.
³ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
⁴ Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
⁵ Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁶ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. Electronic address: sabatini@wi.mit.edu.

Abstract

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.

Keywords: amino acid sensing; autophagy; lysosome; mTOR; micropinocytosis; nutrient sensing.

MeSH terms

Amino Acid Sequence
Amino Acid Transport Systems / chemistry
Amino Acid Transport Systems / genetics
Amino Acid Transport Systems / metabolism*
Amino Acids, Essential / metabolism*
Animals
Arginine / metabolism
Cell Line
Cell Line, Tumor
Humans
Lysosomes / metabolism*
Male
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, Inbred C57BL
Multiprotein Complexes / metabolism*
Sequence Alignment
TOR Serine-Threonine Kinases / metabolism*

Substances

Amino Acid Transport Systems
Amino Acids, Essential
Multiprotein Complexes
SLC38A9 protein, human
SLC38A9 protein, mouse
Arginine
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases

Abstract

MeSH terms

Substances

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