Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1

Science. 2015 Jan 9;347(6218):188-94. doi: 10.1126/science.1257132. Epub 2015 Jan 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Transport Systems / chemistry
  • Amino Acid Transport Systems / genetics
  • Amino Acid Transport Systems / metabolism*
  • Arginine / deficiency
  • Arginine / metabolism*
  • HEK293 Cells
  • Humans
  • Lysosomes / enzymology*
  • Mechanistic Target of Rapamycin Complex 1
  • Molecular Sequence Data
  • Monomeric GTP-Binding Proteins / metabolism*
  • Multiprotein Complexes / metabolism*
  • Protein Structure, Tertiary
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Amino Acid Transport Systems
  • Multiprotein Complexes
  • SLC38A9 protein, human
  • Arginine
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Monomeric GTP-Binding Proteins