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Sestrin2 is a leucine sensor for the mTORC1 pathway
Open accessAbstract
From sensing leucine to metabolic control: The mTORC1 protein kinase complex plays central roles in regulating cell growth and metabolism and is implicated in common human diseases such as diabetes and cancer. The level of the amino acid leucine tells an organism a lot about its physiological state, including how much food is available, how much insulin is going to be needed, and whether new muscle mass can be made (see the Perspective by Buel and Blenis). Wolfson et al. identified a biochemical sensor of leucine, Sestrin2, which connects the concentration of leucine to the control of organismal metabolism and growth. When leucine bound to Sestrin2, it was released from a complex with the mTORC1 regulatory factor GATOR2, activating the mTORC1 complex. Saxton et al. describe the crystal structure of Sestrin2 and show how it specifically detects leucine. Aylett et al. determined the structure of human mTORC1 by cryoelectron microscopy and the crystal structure of a regulatory subunit, Raptor. The results reveal the structural basis for the function and intricate regulation of this important enzyme, which is also a strategic drug target. Science , this issue p. 43 , p. 48 , p. 53 ; see also p. 25
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“Specifically, the Sestrin family of proteins binds to and inhibits the action of GATOR2 when leucine levels are low, permitting GATOR1 to inhibit the recruitment of mTORC1 to the lysosome. Binding of leucine by the Sestrins, particularly Sestrin 2, relieves this inhibition of GATOR2, resulting in the inhibition of GATOR1 GAP activity, and allowing mTORC1 to be recruited to the lysosome 162,169.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [169]
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“Specifically, the Sestrin family of proteins binds to and inhibits the action of GATOR2 when leucine levels are low, permitting GATOR1 to inhibit the recruitment of mTORC1 to the lysosome. Binding of leucine by the Sestrins, particularly Sestrin 2, relieves this inhibition of GATOR2, resulting in the inhibition of GATOR1 GAP activity, and allowing mTORC1 to be recruited to the lysosome 162,169.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [169]
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“and by leucine, which binds to the leucine sensors sestrin 1/2 [174, 175]”
From Effects of Skeletal Muscle Hypertrophy on Fat Mass and Glucose Homeostasis in Humans and Animals: A Narrative Review with Systematic Literature Search (2025) · cites this paper as [174]
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Self-citationThe Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
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Self-citationSancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A. L., Nada, S., & Sabatini, D. M. (2010) · Cell · doi:10.1016/j.cell.2010.02.024 · Cited by 2,464 · cited 5×
“Ragulator anchors the Rag heterodimers to the lysosome and has nucleotide exchange activity for RagA and RagB (21, 25).”
BackgroundInfluentialSelf-citationThe Effect of Retarded Growth Upon the Length of Life Span and Upon the Ultimate Body Size
McCay, C. M., Crowell, M. F., & Maynard, L. A. (1935) · The Journal of Nutrition · doi:10.1093/jn/10.1.63 · Cited by 2,264
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p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling
Budanov, A. V., & Karin, M. (2008) · Cell · doi:10.1016/j.cell.2008.06.028 · Cited by 1,326
Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., & Sabatini, D. M. (2013) · Science · doi:10.1126/science.1232044 · Cited by 1,080 · cited 7×
“Ragulator anchors the Rag heterodimers to the lysosome and has nucleotide exchange activity for RagA and RagB (21, 25).”
BackgroundInfluentialSelf-citationBranched-Chain Amino Acid Metabolism
Harper, A. E., Miller, R. H., & Block, K. P. (1984) · Annual Review of Nutrition · doi:10.1146/annurev.nu.04.070184.002205 · Cited by 1,011
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mTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555
Self-citationGuidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1
Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,897
mTOR at the nexus of nutrition, growth, ageing and disease
Liu, G. Y., & Sabatini, D. M. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0199-y · Cited by 2,737
Self-citationD’Hulst, G., Soro-Arnaiz, I., Masschelein, E., Veys, K., Fitzgerald, G., Smeuninx, B., Kim, S., Deldicque, L., Blaauw, B., Carmeliet, P., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13889-6 · Cited by 2,310
From Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119
Metadata
- Authors
- Wolfson, R. L., Chantranupong, L., Saxton, R. A., Shen, K., Scaria, S. M., Cantor, J. R., & Sabatini, D. M.
- Affiliations
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wolfson, Rachel L.
- Chantranupong, Lynne
- Sabatini, David M.
- ORCID
- Venue
- Science
- Published
- 2016-01
- Volume
- 351
- Issue
- 6268
- Pages
- 43-48
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4698017
- OpenAlex
- W2206269655
- Cited by
- 1,306
- References
- 47
- Citations by year
- 2026: 121 · 2025: 132 · 2024: 126 · 2023: 127 · 2022: 145 · 2021: 154 · 2020: 128 · 2019: 85 · 2018: 103 · 2017: 94 · 2016: 86
- FWCI
- 41.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Department of Defense (W81XWH-07-0448)
- NIH (R01 CA103866, AI47389, T32 GM007753, F30 CA189333, F31 CA180271)
- Paul Gray Undergraduate Research Opportunities Program Fund (3143900)
- Pfizer Fellow of the Life Sciences Research Foundation
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- Sestrin2, leucine sensing, mTORC1, GATOR2, amino acid signaling, raptors, cell growth regulation, metabolic control, therapeutic target
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Sestrins, Humans, Leucine, Nuclear Proteins, Protein Binding, Proteins, Signal Transduction, GTPase-Activating Proteins, Multiprotein Complexes, Metabolic Networks and Pathways, HEK293 Cells, TOR Serine-Threonine Kinases
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