Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling
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Mechanistic target of rapamycin complex 1 (mTORC1) integrates diverse environmental signals to control cellular growth and organismal homeostasis. In response to nutrients, Rag GTPases recruit mTORC1 to the lysosome to be activated, but how Rags are regulated remains incompletely understood. Here, we show that Sestrins bind to the heterodimeric RagA/B-RagC/D GTPases, and function as guanine nucleotide dissociation inhibitors (GDIs) for RagA/B. Sestrin overexpression inhibits amino-acid-induced Rag guanine nucleotide exchange and mTORC1 translocation to the lysosome. Mutation of the conserved GDI motif creates a dominant-negative form of Sestrin that renders mTORC1 activation insensitive to amino acid deprivation, whereas a cell-permeable peptide containing the GDI motif inhibits mTORC1 signaling. Mice deficient in all Sestrins exhibit reduced postnatal survival associated with defective mTORC1 inactivation in multiple organs during neonatal fasting. These findings reveal a nonredundant mechanism by which the Sestrin family of GDIs regulates the nutrient-sensing Rag GTPases to control mTORC1 signaling.
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The mechanisms exposed above are distinct from another sestrin-inhibitory complex, containing GATOR and RAG A/B GTPase, that involves the mTOR pathway.
“The mechanisms exposed above are distinct from another sestrin-inhibitory complex, containing GATOR and RAG A/B GTPase that involves the mTOR pathway (197–199).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [198]
SESN2 has been suggested to act as a guanine nucleotide dissociation inhibitor for RagA, but subsequent structural studies have not supported this hypothesis, and RagA/B-GDI activity remains unproven.
“It has alternatively been suggested to act as a guanine nucleotide dissociation inhibitor (GDI) for RagA (Peng et al., 2014) however subsequent structural studies have not supported this hypothesis.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Peng et al., 2014
Ectopic SESN2 expression prevents mTORC1 localization to the lysosome in the presence of amino acids, while reducing GATOR1-GATOR2 and increasing GATOR1-RagB association, hence acting as a negative regulator of mTORC1 signaling.
“Ectopic SESN2 expression prevents mTORC1 localization to the lysosome in the presence of amino acids (Parmigiani et al., 2014; Peng et al., 2014), while reducing GATOR1-GATOR2, and increasing GATOR1-RagB, association (Kim J S et al., 2015), hence acting as a negative regulator of mTORC1 signaling.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Peng et al., 2014
Several human proteins are now recognized as key metabolite sensors for the mTORC1 pathway: SESN1 and SESN2, CASTOR1, and SAMTOR, and may also include SLC38A9 and the vacuolar (v)-ATPase.
“However, several human proteins are now recognized as key metabolite sensors for the mTORC1 pathway. These include SESN1 and SESN2 (Chantranupong et al., 2014; Parmigiani et al., 2014; Peng et al., 2014), CASTOR1 (Chantranupong et al., 2016), and SAMTOR (Gu et al., 2017), and may also include SLC38A9 (Jung et al., 2015; Rebsamen et al., 2015; Wang et al., 2015) and the vacuolar (v)-ATPase (Zoncu”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Peng et al., 2014
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References 54 · Cited by 220
- Authors
- Peng, M., Yin, N., & Li, M. O.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Li, Ming O.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 159
- Issue
- 1
- Pages
- 122-133
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4181352
- OpenAlex
- W2047612586
- Cited by
- 220
- References
- 54
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 10 · 2023: 21 · 2022: 22 · 2021: 17 · 2020: 23 · 2019: 22 · 2018: 16 · 2017: 20 · 2016: 24 · 2015: 28 · 2014: 4
- FWCI
- 10.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA008748)
- National Institute of Allergy and Infectious Diseases (R01AI102888)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- sestrins, guanine nucleotide dissociation inhibitor, Rag GTPases, mTORC1 signaling, amino acid signaling, nutrient sensing, lysosomal translocation, postnatal survival, cell growth regulation
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 2 Protein, Sestrins, Amino Acid Sequence, Amino Acids, Animals, Animals, Newborn, Embryo, Mammalian, Female, Fibroblasts, Heat-Shock Proteins, Molecular Sequence Data, Nuclear Proteins, Peroxidases, Pregnancy, Starvation, Signal Transduction, Sequence Alignment, Mice, Knockout, Cell Cycle Proteins, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, Multiprotein Complexes, Mice, AMP-Activated Protein Kinases, Gene Knock-In Techniques, TOR Serine-Threonine Kinases
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