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.

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
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1