O-GlcNAcylation of Raptor transduces glucose signals to mTORC1

Chenchen Xu; Xiaoqing Pan; Dong Wang; Yuanyuan Guan; Wenyu Yang; Xing Chen; Ying Liu

doi:10.1016/j.molcel.2023.07.011

O-GlcNAcylation of Raptor transduces glucose signals to mTORC1

Mol Cell. 2023 Aug 17;83(16):3027-3040.e11. doi: 10.1016/j.molcel.2023.07.011. Epub 2023 Aug 3.

Authors

Chenchen Xu¹, Xiaoqing Pan², Dong Wang¹, Yuanyuan Guan¹, Wenyu Yang³, Xing Chen⁴, Ying Liu⁵

Affiliations

¹ State Key Laboratory of Membrane Biology, New Cornerstone Science Laboratory, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China.
² College of Chemistry and Molecular Engineering, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
³ Yuan Pei College, Peking University, Beijing 100871, China.
⁴ College of Chemistry and Molecular Engineering, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Beijing National Laboratory for Molecular Sciences, Peking University, Beijing 100871, China; Synthetic and Functional Biomolecules Center, Peking University, Beijing 100871, China; Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking University, Beijing 100871, China. Electronic address: xingchen@pku.edu.cn.
⁵ State Key Laboratory of Membrane Biology, New Cornerstone Science Laboratory, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Beijing Advanced Innovation Center for Genomics, Beijing 100871, China. Electronic address: ying.liu@pku.edu.cn.

PMID: 37541260
DOI: 10.1016/j.molcel.2023.07.011

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient levels. Dysregulation of mTORC1 results in a broad spectrum of diseases. Glucose is the primary energy supply of cells, and therefore, glucose levels must be accurately conveyed to mTORC1 through highly responsive signaling mechanisms to control mTORC1 activity. Here, we report that glucose-induced mTORC1 activation is regulated by O-GlcNAcylation of Raptor, a core component of mTORC1, in HEK293T cells. Mechanistically, O-GlcNAcylation of Raptor at threonine 700 facilitates the interactions between Raptor and Rag GTPases and promotes the translocation of mTOR to the lysosomal surface, consequently activating mTORC1. In addition, we show that AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor-Rags interactions. Our findings reveal an exquisitely controlled mechanism, which suggests how glucose coordinately regulates cellular anabolism and catabolism.

Keywords: O-GlcNAcylation; Raptor; glucose sensing; mTOR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing* / genetics
Adaptor Proteins, Signal Transducing* / metabolism
HEK293 Cells
Humans
Mechanistic Target of Rapamycin Complex 1 / genetics
Mechanistic Target of Rapamycin Complex 1 / metabolism
Multiprotein Complexes* / metabolism
Phosphorylation
Regulatory-Associated Protein of mTOR / genetics
Regulatory-Associated Protein of mTOR / metabolism

Substances

Mechanistic Target of Rapamycin Complex 1
Adaptor Proteins, Signal Transducing
Multiprotein Complexes
Regulatory-Associated Protein of mTOR