Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway

Cell. 2012 Apr 13;149(2):410-24. doi: 10.1016/j.cell.2012.02.044. Epub 2012 Mar 15.

Abstract

Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase, which regulates protein translation, cell size, and autophagy. However, the amino acid sensor that directly couples intracellular amino acid-mediated signaling to mTORC1 is unknown. Here we show that leucyl-tRNA synthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation by sensing intracellular leucine concentration and initiating molecular events leading to mTORC1 activation. Mutation of LRS amino acid residues important for leucine binding renders the mTORC1 pathway insensitive to intracellular levels of amino acids. We show that LRS directly binds to Rag GTPase, the mediator of amino acid signaling to mTORC1, in an amino acid-dependent manner and functions as a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1. This work demonstrates that LRS is a key mediator for amino acid signaling to mTORC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autophagy
  • Cell Line
  • Cell Size
  • Humans
  • Leucine / metabolism*
  • Leucine-tRNA Ligase / chemistry
  • Leucine-tRNA Ligase / metabolism*
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Molecular Sequence Data
  • Multiprotein Complexes
  • Protein Biosynthesis
  • Proteins / chemistry
  • Proteins / metabolism*
  • Sequence Alignment
  • Signal Transduction*
  • TOR Serine-Threonine Kinases

Substances

  • Multiprotein Complexes
  • Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Leucine-tRNA Ligase
  • Leucine