SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1

Nature. 2015 Mar 26;519(7544):477-81. doi: 10.1038/nature14107. Epub 2015 Jan 7.

Abstract

Cell growth and proliferation are tightly linked to nutrient availability. The mechanistic target of rapamycin complex 1 (mTORC1) integrates the presence of growth factors, energy levels, glucose and amino acids to modulate metabolic status and cellular responses. mTORC1 is activated at the surface of lysosomes by the RAG GTPases and the Ragulator complex through a not fully understood mechanism monitoring amino acid availability in the lysosomal lumen and involving the vacuolar H(+)-ATPase. Here we describe the uncharacterized human member 9 of the solute carrier family 38 (SLC38A9) as a lysosomal membrane-resident protein competent in amino acid transport. Extensive functional proteomic analysis established SLC38A9 as an integral part of the Ragulator-RAG GTPases machinery. Gain of SLC38A9 function rendered cells resistant to amino acid withdrawal, whereas loss of SLC38A9 expression impaired amino-acid-induced mTORC1 activation. Thus SLC38A9 is a physical and functional component of the amino acid sensing machinery that controls the activation of mTOR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems / metabolism*
  • Amino Acids / metabolism*
  • Animals
  • Cell Line
  • Humans
  • Lysosomes / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Monomeric GTP-Binding Proteins / metabolism
  • Multiprotein Complexes / metabolism*
  • Nucleotides / metabolism
  • TOR Serine-Threonine Kinases / metabolism*

Substances

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