Metabolic Stress Controls mTORC1 Lysosomal Localization and Dimerization by Regulating the TTT-RUVBL1/2 Complex
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The metabolism of glucose and glutamine, primary carbon sources utilized by mitochondria to generate energy and macromolecules for cell growth, is directly regulated by mTORC1. We show that glucose and glutamine, by supplying carbons to the TCA cycle to produce ATP, positively feed back to mTORC1 through an AMPK-, TSC1/2-, and Rag-independent mechanism by regulating mTORC1 assembly and its lysosomal localization. We discovered that the ATP-dependent TTT-RUVBL1/2 complex was disassembled and repressed by energy depletion, resulting in its decreased interaction with mTOR. The TTT-RUVBL complex was necessary for the interaction between mTORC1 and Rag and formation of mTORC1 obligate dimers. In cancer tissues, TTT-RUVBL complex mRNAs were elevated and positively correlated with transcripts encoding proteins of anabolic metabolism and mitochondrial function-all mTORC1-regulated processes. Thus, the TTT-RUVBL1/2 complex responds to the cell's metabolic state, directly regulating the functional assembly of mTORC1 and indirectly controlling the nutrient signal from Rags to mTORC1.
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In some cells, metabolic stress inhibits mTOR in an AMPK-independent manner by preventing mTOR localization to the lysosome.
“More recently, a third group has shown that in some cells, metabolic stress inhibits mTOR in an AMPK-independent manner by preventing mTOR localization to the lysosome [45].”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [45]
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- Authors
- Kim, S. G., Hoffman, G. R., Poulogiannis, G., Buel, G. R., Jang, Y. J., Lee, K. W., Kim, B.-Y., Erikson, R. L., Cantley, L. C., Choo, A. Y., & Blenis, J.
- Affiliations
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Seoul National University (KR)
- Korea Research Institute of Bioscience and Biotechnology (KR)
- Corresponding author
- Choo, Andrew Y.
- Blenis, John
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 49
- Issue
- 1
- Pages
- 172-185
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3545014
- OpenAlex
- W2004768888
- Cited by
- 215
- References
- 42
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 14 · 2023: 13 · 2022: 15 · 2021: 20 · 2020: 25 · 2019: 16 · 2018: 14 · 2017: 15 · 2016: 12 · 2015: 21 · 2014: 20 · 2013: 11 · 2012: 1
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 374 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- KRIBB Repository (submittedVersion)
- Funders
- National Institutes of Health (RO1GM051405)
- National Research Foundation of Korea
- Tuberous Sclerosis Alliance
- U.S. Department of Defense (W81XWH-10-1-0555)
- 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
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mTORC1, lysosomal localization, metabolic stress, glucose metabolism, glutamine metabolism, TCA cycle, Rag GTPases, energy depletion, AMPK, TSC1/2, cancer metabolism, mitochondrial function
- MeSH terms
- ATPases Associated with Diverse Cellular Activities, Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Adenosine Triphosphate, Adenylate Kinase, Animals, Breast Neoplasms, Carcinoma, Carrier Proteins, Cells, Cultured, Citric Acid Cycle, DNA Helicases, Energy Metabolism, Female, Glucose, Glutamine, Humans, Lysosomes, Protein Binding, Proteins, Stress, Physiological, Signal Transduction, Mice, Knockout, Statistics, Nonparametric, Monomeric GTP-Binding Proteins, Protein Transport, Tumor Suppressor Proteins, Telomere-Binding Proteins, Ribosomal Protein S6 Kinases, 90-kDa, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Mice, Protein Multimerization, TOR Serine-Threonine Kinases
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