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Glucose-dependent control of leucine metabolism by leucyl-tRNA synthetase 1

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Science  10 Jan 2020:
Vol. 367, Issue 6474, pp. 205-210
DOI: 10.1126/science.aau2753

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A tRNA synthase in metabolic control

Leucyl-tRNA synthetase 1 (LARS1), which covalently couples leucine to its cognate transfer RNAs (tRNAs), appears to have broader roles in the control of leucine metabolism. The enzyme also serves as a leucine sensor for the mechanistic target of rapamycin complex 1 (mTORC1), which regulates protein synthesis, metabolism, autophagy, and cell growth. Yoon et al. show that in cells deprived of glucose, LARS1 is phosphorylated by Unc-51 like autophagy activating kinase 1 (see the Perspective by Lehman and Abraham). This phosphorylation decreases leucine binding to LARS1 and, in turn, should decrease translation, reduce activation of mTORC1, and perhaps free up leucine for use in the generation of adenosine triphosphate in glucose-starved cells.

Science, this issue p. 205; see also p. 146

Abstract

Despite the importance of glucose and amino acids for energy metabolism, interactions between the two nutrients are not well understood. We provide evidence for a role of leucyl-tRNA synthetase 1 (LARS1) in glucose-dependent control of leucine usage. Upon glucose starvation, LARS1 was phosphorylated by Unc-51 like autophagy activating kinase 1 (ULK1) at the residues crucial for leucine binding. The phosphorylated LARS1 showed decreased leucine binding, which may inhibit protein synthesis and help save energy. Leucine that is not used for anabolic processes may be available for catabolic pathway energy generation. The LARS1-mediated changes in leucine utilization might help support cell survival under glucose deprivation. Thus, depending on glucose availability, LARS1 may help regulate whether leucine is used for protein synthesis or energy production.

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