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 and Jung Min Han ()
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Kibum Kim: Yonsei University
Hee Chan Yoo: Yonsei University
Byung Gyu Kim: Institute for Basic Science
Sulhee Kim: Korea University
Yulseung Sung: Yonsei University
Ina Yoon: Yonsei University
Ya Chun Yu: Yonsei University
Seung Joon Park: Yonsei University
Jong Hyun Kim: Catholic University of Daegu
Kyungjae Myung: Institute for Basic Science
Kwang Yeon Hwang: Korea University
Sunghoon Kim: Yonsei University
Jung Min Han: Yonsei University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30696-8

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