Sestrins inhibit mTORC1 kinase activation through the GATOR complex
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The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a sensor of different environmental conditions and regulator of cell growth, metabolism, and autophagy. mTORC1 is activated by Rag GTPases, working as RagA:RagB and RagC:RagD heterodimers. Rags control mTORC1 activity by tethering mTORC1 to the lysosomes where it is activated by Rheb GTPase. RagA:RagB, active in its GTP-bound form, is inhibited by GATOR1 complex, a GTPase-activating protein, and GATOR1 is in turn negatively regulated by GATOR2 complex. Sestrins are stress-responsive proteins that inhibit mTORC1 via activation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex. Here we report an AMPK-independent mechanism of mTORC1 inhibition by Sestrins mediated by their interaction with GATOR2. As a result of this interaction, the Sestrins suppress mTOR lysosomal localization in a Rag-dependent manner. This mechanism is potentially involved in mTORC1 regulation by amino acids, rotenone, and tunicamycin, connecting stress response with mTORC1 inhibition.
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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 [197]
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 Parmigiani et al., 2014
SESN2 interacts with GATOR2, with the interaction conditionally strengthened by both amino acid deprivation and DNA damage-induced stress.
“SESN2 interacts with GATOR2 (Chantranupong et al., 2014; Parmigiani et al., 2014; Kim J S et al., 2015), with the interaction conditionally strengthened by both amino acid deprivation (Chantranupong et al., 2014) and DNA damage-induced stress (Parmigiani et al., 2014).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Parmigiani 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 Parmigiani et al., 2014
WDR24 and SEH1L form a minimal complex sufficient for interaction with SESN2, and these GATOR2 components with the addition of MIOS are sufficient to bind CASTOR1.
“WDR24 and SEH1L are known to form a minimal complex sufficient for interaction with SESN2 (Parmigiani et al., 2014), and these GATOR2 components, with the addition of MIOS, were also identified as sufficient to bind CASTOR1 (Chantranupong et al., 2016; Gai et al., 2016b).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Parmigiani et al., 2014
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References 34 · Cited by 336
- Authors
- Parmigiani, A., Nourbakhsh, A., Ding, B., Wang, W., Kim, Y. C., Akopiants, K., Guan, K.-L., Karin, M., & Budanov, A. V.
- Affiliations
- Virginia Commonwealth University (US)
- University of California San Diego (US)
- Corresponding author
- Budanov, Andrei V.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 9
- Issue
- 4
- Pages
- 1281-1291
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4303546
- OpenAlex
- W1993506872
- Cited by
- 336
- References
- 34
- Citations by year
- 2026: 9 · 2025: 22 · 2024: 19 · 2023: 25 · 2022: 29 · 2021: 36 · 2020: 42 · 2019: 31 · 2018: 32 · 2017: 31 · 2016: 32 · 2015: 28
- FWCI
- 12.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Arrow@dit (Dublin Institute of Technology) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA172660, R01CA108941, R01CA155120)
- National Institute of Environmental Health Sciences (P42ES010337)
- 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, mTORC1, GATOR1 complex, Rag GTPases, amino acid signaling, rotenone, tunicamycin, stress response, tuberous sclerosis complex
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Sestrins, Amino Acids, Animals, Enzyme Activation, Humans, Lysosomes, Nuclear Proteins, Peroxidases, Phosphorylation, Protein Binding, Rotenone, Tunicamycin, Signal Transduction, GTP Phosphohydrolases, Protein Transport, Ribosomal Protein S6 Kinases, 70-kDa, Multiprotein Complexes, Mice, AMP-Activated Protein Kinases, HEK293 Cells, TOR Serine-Threonine Kinases
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