Leucyl-tRNA Synthetase Is an Intracellular Leucine Sensor for the mTORC1-Signaling Pathway

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.

Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS

“…However, LARS has recently been shown to be an activator of mTORC1, the latter of which inhibits autophagy (Han et al 2012). Autophagy is an important quality-control mechanism in the human body that serves to degrade long-lived and damaged cytoplasmic organelles to generate new substrates for energy production.…”

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

“…30-32 In addition, leucyl-tRNA synthetase (LRS), which uses tRNA Leu as the substrate, has also been reported to be a leucine sensor of mTOR, 33 , 34 which is another reason to explore the relation between tRNA Leu and the mTOR pathway. Therefore, we investigated the phosphorylation of p70 S6K and 4E-BP (eukaryotic translation initiation factor 4E binding protein), both of which are key effectors of mTOR signaling.…”

dRAGging Amino Acid-mTORC1 Signaling by SH3BP4

“…Recently, LRS was shown to interact with Rag GTPases and mediate leucine signaling to Rag GTPases (Han et al, 2012). The interaction is enhanced under leucine-enriched conditions and is crucial to activate mTORC1.…”

“…LRS has a preferential binding affinity toward GTP-charged RagD. LRS has a putative GTPase-activating protein (GAP) motif and a GAP activity toward RagD in response to leucine (Han et al, 2012). The conversion of GTP-charged RagD to GDP-charged RagD enhances the capacity of Rag GTPase complex to activate mTORC1.…”