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

Ze'ev Ronai

Ze'ev Ronai

Ze'ev Ronai

Jianfei Qi

Jianfei Qi

Jianfei Qi

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This study reveals a novel role of leucyl-tRNA synthetase (LRS) as a sensor for the amino acid leucine, and activator of the Rag GTPases and mammalian target of rapamycin 1 (mTOR1) signaling. Growth factors and intracellular energy levels are known to regulate mTOR1 activity via tuberous sclerosis protein (TSC)1/2. In contrast, amino acids, primarily leucine, activate mTOCR1 independent of TSC1/2 but dependent on Rag GTPases, which are located on lysosomes, and mediate the recruitment and subsequent activation of mTOR1 on lysosomes. However, it remains unclear how amino acids transmit signals to Rag GTPases. In this paper, Han et al. identified LRS as a leucine sensor to mediate the signaling of amino acids to Rag GTPases and mTOR1. LRS is found to interact with Rag GTPases or mTOR1 in a leucine-dependent manner. The LRS-Rag GTPase interaction depends on the leucine-binding capability of LRS, and is critical for amino acid- or leucine-induced activation of mTOR1. LRS also functions as a potential GTPase-activating protein (GAP) for activation of the Rag GTPase heterodimer that is required for the mTOR1 activation. This study reveals a novel role of LRS as a sensor and transducer of amino acid signals for the mTOR1 pathway.

Aurelio Teleman

Aurelio Teleman

Aurelio Teleman

Constantinos Demetriades

Constantinos Demetriades

Constantinos Demetriades

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The mammalian target of rapamycin complex 1 (mTORC1) functions as an intracellular sensor for amino acids, linking their availability to cell growth, protein synthesis and autophagy. Despite the increasing number of publications in the last 4 years, identifying components of the amino acid pathway to mTORC1 (mostly the Rag GTPases and their interacting proteins) and the mechanistic details that have been described, proteins that would function as direct sensors for amino acids have so far not been discovered. The GTP/GDP loading of the Rag complex plays a crucial role on mTORC1 recruitment on intracellular compartments, where its activator Rheb is present. However, there was a gap in our knowledge of how amino acids regulate GTP/GDP loading of this complex, until now. In this intriguing study, Han et al. provide novel insight on this fundamental question by identifying the Leucyl-tRNA Synthetase (LRS) as a protein that interacts with and functions as a GTPase-activating protein (GAP) for RagD (but not RagA, RagB or RagC) when bound to leucine. The GAP activity of LRS keeps RagD in the active GDP-bound state and facilitates mTORC1 localization to intracellular membrane compartments, linking directly the availability of this amino acid to mTORC1 activation for the first time. These findings were strengthened further by an independent study in yeast, published by Bonfils et al. {1} synchronously to this work, which also proposed an important role for LRS in leucine sensing and TORC1 activation. In this excellent paper, it was proposed that it is the amino acid-editing activity of LRS that 'recognizes' the absence of leucine and signals to TORC1 by binding to Gtr1 (the RagA/RagB homologue in yeast) and modifying its GTP status. Despite the mechanistic differences between the two papers, they both suggest a non-canonical function for LRS, which interacts with the Rag complex in response to leucine, modifies its GTP/GDP status and affects TORC1 localization and activity. Further work will be necessary to shed light on the nature of the discrepancies between the two papers and to identify the exact mechanism by which leucine and other amino acids signal to TORC1. Given the importance of TORC1 activity for the regulation of cell growth and its deregulation in several types of cancers or metabolic diseases, these studies might reveal novel targets with a potential for the development of new therapeutic approaches.

Peter Taylor

Peter Taylor

Peter Taylor

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This paper reveals that a substantial component of leucyl-tRNA synthetase (LRS) in mammalian cells is associated with intracellular membranes (in sharp contrast to the cytosolic localization of other aminoacyl-tRNA synthetases), where its leucine-binding motif acts as part of a nutrient sensor upstream of the target of rapamycin complex 1 (mTORC1) signalling pathway. LRS binds to Rag GTPase in an amino acid-dependent manner and acts as a GTPase-activating protein for RagD GTPase, which is a prerequisite for mTORC1 activation. The findings help explain the "primacy" of leucine as the mTORC1-activating nutrient whilst, because the leucine-binding site on LRS appears to recognise several noncognate amino acids (e.g. isoleucine) and leucine analogues with low-affinity, allowing for selective mTORC1 activation by other related compounds.