O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine

Kibum Kim; Hee Chan Yoo; Byung Gyu Kim; Sulhee Kim; Yulseung Sung; Ina Yoon; Ya Chun Yu; Seung Joon Park; Jong Hyun Kim; Kyungjae Myung; Kwang Yeon Hwang; Sunghoon Kim; Jung Min Han

doi:10.1038/s41467-022-30696-8

O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine

Kibum Kim, Hee Chan Yoo, Byung Gyu Kim, Sulhee Kim, Yulseung Sung, Ina Yoon, Ya Chun Yu, Seung Joon Park, Jong Hyun Kim, Kyungjae Myung, Kwang Yeon Hwang, Sunghoon Kim, Jung Min Han

Department of Biosystems and Biotechnology

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

All living organisms have the ability to sense nutrient levels to coordinate cellular metabolism. Despite the importance of nutrient-sensing pathways that detect the levels of amino acids and glucose, how the availability of these two types of nutrients is integrated is unclear. Here, we show that glucose availability regulates the central nutrient effector mTORC1 through intracellular leucine sensor leucyl-tRNA synthetase 1 (LARS1). Glucose starvation results in O-GlcNAcylation of LARS1 on residue S1042. This modification inhibits the interaction of LARS1 with RagD GTPase and reduces the affinity of LARS1 for leucine by promoting phosphorylation of its leucine-binding site by the autophagy-activating kinase ULK1, decreasing mTORC1 activity. The lack of LARS1 O-GlcNAcylation constitutively activates mTORC1, supporting its ability to sense leucine, and deregulates protein synthesis and leucine catabolism under glucose starvation. This work demonstrates that LARS1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine.

Original language	English
Article number	2904
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30696-8
Publication status	Published - 2022 Dec

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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Kim, K., Yoo, H. C., Kim, B. G., Kim, S., Sung, Y., Yoon, I., Yu, Y. C., Park, S. J., Kim, J. H., Myung, K., Hwang, K. Y., Kim, S., & Han, J. M. (2022). O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine. Nature communications, 13(1), [2904]. https://doi.org/10.1038/s41467-022-30696-8

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title = "O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine",

abstract = "All living organisms have the ability to sense nutrient levels to coordinate cellular metabolism. Despite the importance of nutrient-sensing pathways that detect the levels of amino acids and glucose, how the availability of these two types of nutrients is integrated is unclear. Here, we show that glucose availability regulates the central nutrient effector mTORC1 through intracellular leucine sensor leucyl-tRNA synthetase 1 (LARS1). Glucose starvation results in O-GlcNAcylation of LARS1 on residue S1042. This modification inhibits the interaction of LARS1 with RagD GTPase and reduces the affinity of LARS1 for leucine by promoting phosphorylation of its leucine-binding site by the autophagy-activating kinase ULK1, decreasing mTORC1 activity. The lack of LARS1 O-GlcNAcylation constitutively activates mTORC1, supporting its ability to sense leucine, and deregulates protein synthesis and leucine catabolism under glucose starvation. This work demonstrates that LARS1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine.",

author = "Kibum Kim and Yoo, {Hee Chan} and Kim, {Byung Gyu} and Sulhee Kim and Yulseung Sung and Ina Yoon and Yu, {Ya Chun} and Park, {Seung Joon} and Kim, {Jong Hyun} and Kyungjae Myung and Hwang, {Kwang Yeon} and Sunghoon Kim and Han, {Jung Min}",

note = "Funding Information: This work was supported by the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education (2018R1A6A1A03023718, 2020R1I1A1A01067423), the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (2020M3E5E2040282), and a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science & ICT (MSIT) (2020R1A2C2099586, 2021R1C1C2006283). Y.S was supported by the Health Fellowship Foundation. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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doi = "10.1038/s41467-022-30696-8",

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AU - Kim, Kibum

AU - Yoo, Hee Chan

AU - Kim, Byung Gyu

AU - Kim, Sulhee

AU - Sung, Yulseung

AU - Yoon, Ina

AU - Yu, Ya Chun

AU - Park, Seung Joon

AU - Kim, Jong Hyun

AU - Myung, Kyungjae

AU - Hwang, Kwang Yeon

AU - Kim, Sunghoon

AU - Han, Jung Min

N1 - Funding Information: This work was supported by the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education (2018R1A6A1A03023718, 2020R1I1A1A01067423), the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (2020M3E5E2040282), and a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science & ICT (MSIT) (2020R1A2C2099586, 2021R1C1C2006283). Y.S was supported by the Health Fellowship Foundation. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - All living organisms have the ability to sense nutrient levels to coordinate cellular metabolism. Despite the importance of nutrient-sensing pathways that detect the levels of amino acids and glucose, how the availability of these two types of nutrients is integrated is unclear. Here, we show that glucose availability regulates the central nutrient effector mTORC1 through intracellular leucine sensor leucyl-tRNA synthetase 1 (LARS1). Glucose starvation results in O-GlcNAcylation of LARS1 on residue S1042. This modification inhibits the interaction of LARS1 with RagD GTPase and reduces the affinity of LARS1 for leucine by promoting phosphorylation of its leucine-binding site by the autophagy-activating kinase ULK1, decreasing mTORC1 activity. The lack of LARS1 O-GlcNAcylation constitutively activates mTORC1, supporting its ability to sense leucine, and deregulates protein synthesis and leucine catabolism under glucose starvation. This work demonstrates that LARS1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine.

AB - All living organisms have the ability to sense nutrient levels to coordinate cellular metabolism. Despite the importance of nutrient-sensing pathways that detect the levels of amino acids and glucose, how the availability of these two types of nutrients is integrated is unclear. Here, we show that glucose availability regulates the central nutrient effector mTORC1 through intracellular leucine sensor leucyl-tRNA synthetase 1 (LARS1). Glucose starvation results in O-GlcNAcylation of LARS1 on residue S1042. This modification inhibits the interaction of LARS1 with RagD GTPase and reduces the affinity of LARS1 for leucine by promoting phosphorylation of its leucine-binding site by the autophagy-activating kinase ULK1, decreasing mTORC1 activity. The lack of LARS1 O-GlcNAcylation constitutively activates mTORC1, supporting its ability to sense leucine, and deregulates protein synthesis and leucine catabolism under glucose starvation. This work demonstrates that LARS1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine.

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O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine

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