1. O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine
- Author
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Kim, Kibum, Yoo, Hee Chan, Kim, Byung Gyu, Kim, Sulhee, Sung, Yulseung, Yoon, Ina, Yu, Ya Chun, Park, Seung Joon, Kim, Jong Hyun, Myung, Kyungjae, Hwang, Kwang Yeon, Kim, Sunghoon, and Han, Jung Min
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Diabetes ,Nutrition ,Underpinning research ,1.1 Normal biological development and functioning ,Metabolic and endocrine ,Acetylglucosamine ,Autophagy ,Glucose ,Humans ,Leucine ,Leucine-tRNA Ligase ,Mechanistic Target of Rapamycin Complex 1 - 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.
- Published
- 2022