SAR1B senses leucine levels to regulate mTORC1 signalling

Jie Chen; Yuhui Ou; Rong Luo; Jie Wang; Dong Wang; Jialiang Guan; Yi Li; Peixue Xia; Peng R Chen; Ying Liu

doi:10.1038/s41586-021-03768-w

SAR1B senses leucine levels to regulate mTORC1 signalling

Nature. 2021 Aug;596(7871):281-284. doi: 10.1038/s41586-021-03768-w. Epub 2021 Jul 21.

Authors

Jie Chen^#^{1

2}, Yuhui Ou^#³, Rong Luo⁴, Jie Wang⁵, Dong Wang³, Jialiang Guan⁴, Yi Li^{3

6}, Peixue Xia⁶, Peng R Chen^{6

5}, Ying Liu^{7

8

9}

Affiliations

¹ State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China. chen.jie@pku.edu.cn.
² Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. chen.jie@pku.edu.cn.
³ State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China.
⁴ PKU-Tsinghua-NIBS Graduate Program, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
⁵ Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
⁶ Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
⁷ State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China. ying.liu@pku.edu.cn.
⁸ Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. ying.liu@pku.edu.cn.
⁹ Beijing Advanced Innovation Center for Genomics, Beijing, China. ying.liu@pku.edu.cn.

^# Contributed equally.

PMID: 34290409
DOI: 10.1038/s41586-021-03768-w

Abstract

The mTOR complex 1 (mTORC1) controls cell growth in response to amino acid levels¹. Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its activator GATOR2. In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. SAR1B-GATOR2-mTORC1 signalling is conserved in nematodes and has a role in the regulation of lifespan. Bioinformatic analysis reveals that SAR1B deficiency correlates with the development of lung cancer. The silencing of SAR1B and its paralogue SAR1A promotes mTORC1-dependent growth of lung tumours in mice. Our results reveal that SAR1B is a conserved leucine sensor that has a potential role in the development of lung cancer.

Publication types

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

MeSH terms

Animals
Caenorhabditis elegans / genetics
Caenorhabditis elegans / metabolism
Caenorhabditis elegans / physiology
Caenorhabditis elegans Proteins / genetics
Caenorhabditis elegans Proteins / metabolism
Conserved Sequence
GTP Phosphohydrolases / genetics
GTP Phosphohydrolases / metabolism
HEK293 Cells
Humans
Leucine / deficiency
Leucine / metabolism*
Longevity / genetics
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Mechanistic Target of Rapamycin Complex 1 / agonists
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Mice
Monomeric GTP-Binding Proteins / chemistry
Monomeric GTP-Binding Proteins / deficiency
Monomeric GTP-Binding Proteins / genetics
Monomeric GTP-Binding Proteins / metabolism*
Multiprotein Complexes / metabolism
Nuclear Proteins / metabolism
Protein Binding
Signal Transduction*
Tumor Suppressor Proteins / metabolism
Xenograft Model Antitumor Assays

Substances

Caenorhabditis elegans Proteins
Multiprotein Complexes
Nuclear Proteins
SESN2 protein, human
Tumor Suppressor Proteins
Mechanistic Target of Rapamycin Complex 1
GTP Phosphohydrolases
SAR-1 protein, C elegans
SAR1A protein, human
SAR1B protein, human
Monomeric GTP-Binding Proteins
Leucine