The GATOR-Rag GTPase pathway inhibits mTORC1 activation by lysosome-derived amino acids

Science. 2020 Oct 16;370(6514):351-356. doi: 10.1126/science.aaz0863.

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) couples nutrient sufficiency to cell growth. mTORC1 is activated by exogenously acquired amino acids sensed through the GATOR-Rag guanosine triphosphatase (GTPase) pathway, or by amino acids derived through lysosomal degradation of protein by a poorly defined mechanism. Here, we revealed that amino acids derived from the degradation of protein (acquired through oncogenic Ras-driven macropinocytosis) activate mTORC1 by a Rag GTPase-independent mechanism. mTORC1 stimulation through this pathway required the HOPS complex and was negatively regulated by activation of the GATOR-Rag GTPase pathway. Therefore, distinct but functionally coordinated pathways control mTORC1 activity on late endocytic organelles in response to distinct sources of amino acids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism*
  • Enzyme Activation
  • GTP Phosphohydrolases / metabolism*
  • HEK293 Cells
  • Humans
  • Lysosomes / enzymology*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Pinocytosis
  • Proteolysis
  • R-SNARE Proteins / metabolism*

Substances

  • Amino Acids
  • R-SNARE Proteins
  • VAMP7 protein, human
  • VAMP8 protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • GTP Phosphohydrolases

Grant support