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

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

  • Nat Commun. 2022 May 25;13(1):2904. doi: 10.1038/s41467-022-30696-8.
Kibum Kim  # 1 2,  Hee Chan Yoo  # 2,  Byung Gyu Kim 3,  Sulhee Kim 4,  Yulseung Sung 2,  Ina Yoon 2 5 6,  Ya Chun Yu 2,  Seung Joon Park 1 2,  Jong Hyun Kim 7,  Kyungjae Myung 3 8,  Kwang Yeon Hwang 4,  Sunghoon Kim 2 5 6,  Jung Min Han 9 10 11
Affiliations

Affiliations

  • 1 Interdisciplinary Program of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, 03722, South Korea.
  • 2 Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, 21983, South Korea.
  • 3 Center for Genomic Integrity, Institute for Basic Science, Ulsan, 44919, South Korea.
  • 4 Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, South Korea.
  • 5 Institute for Artificial Intelligence and Biomedical Research, Medicinal Bioconvergence Research Center, Yonsei University, Incheon, 21983, South Korea.
  • 6 College of Medicine, Gangnam Severance Hospital, Yonsei University, Seoul, 06273, South Korea.
  • 7 Department of Biochemistry, School of Medicine, Catholic University of Daegu, Daegu, 42472, South Korea.
  • 8 Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, 44919, South Korea.
  • 9 Interdisciplinary Program of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, 03722, South Korea. [email protected].
  • 10 Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, 21983, South Korea. [email protected].
  • 11 POSTECH Biotech Center, Pohang University of Science and Technology, Pohang, 37673, South Korea. [email protected].
  • # Contributed equally.
PMID: 35614056 DOI: 10.1038/s41467-022-30696-8
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.

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