Leucyl-tRNA Synthetase Is an Intracellular Leucine Sensor for the mTORC1-Signaling Pathway
Open accessAbstract
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.
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LRS may serve as a GTPase activating protein towards RagD, a component of the RagA/B and RagC/D heterodimer important for amino acid sensing.
“LRS may serve as a GTPase activating protein (GAP) towards the small G-protein (RagD), which in turn is a component of a heterodimer of RagA/B and RagC/D that is important for amino acid sensing.”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [20]
Leucine binds to leucyl-tRNA synthetase, which conjugates leucine to its tRNAs and acts as the first step in the amino acid activation of mTORC1.
“As leucine is taken up, it binds to the leucyl-transfer RNA (tRNA) synthetase (LRS). This not only conjugates leucine to its tRNAs, but the LRS also acts as the first step in the amino acid activation of the mTORC1 [20].”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [20]
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- Authors
- Han, J. M., Jeong, S. J., Park, M. C., Kim, G., Kwon, N. H., Kim, H. K., Ha, S. H., Ryu, S. H., & Kim, S.
- Affiliations
- Seoul National University (KR)
- Pohang University of Science and Technology (KR)
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 149
- Issue
- 2
- Pages
- 410-424
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2056664023
- Cited by
- 824
- References
- 1
- Citations by year
- 2026: 36 · 2025: 41 · 2024: 46 · 2023: 41 · 2022: 55 · 2021: 60 · 2020: 68 · 2019: 56 · 2018: 61 · 2017: 57 · 2016: 70 · 2015: 63 · 2014: 68 · 2013: 63 · 2012: 39
- FWCI
- 29.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Open Access System for Information Sharing (Pohang University of Science and Technology) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- leucyl-tRNA synthetase, mTORC1, amino acid signaling, leucine sensing, Rag GTPases, GTPase-activating protein, amino acid binding, translational regulation, autophagy, cell size control
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Amino Acid Sequence, Animals, Autophagy, Cell Line, Humans, Leucine, Leucine-tRNA Ligase, Lysosomes, Molecular Sequence Data, Proteins, Protein Biosynthesis, Signal Transduction, Sequence Alignment, Multiprotein Complexes, Cell Size, TOR Serine-Threonine Kinases
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