The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A
Open accessAbstract
The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell growth and metabolism. Leucine (Leu) activates mTORC1 and many have tried to identify the mechanisms whereby cells sense Leu in this context. Here we describe that the Leu metabolite acetyl-coenzyme A (AcCoA) positively regulates mTORC1 activity by EP300-mediated acetylation of the mTORC1 regulator, Raptor, at K1097. Leu metabolism and consequent mTORC1 activity are regulated by intermediary enzymes. As AcCoA is a Leu metabolite, this process directly correlates with Leu abundance, and does not require Leu sensing via intermediary proteins, as has been described previously. Importantly, we describe that this pathway regulates mTORC1 in a cell-type-specific manner. Finally, we observed decreased acetylated Raptor, and inhibited mTORC1 and EP300 activity in fasted mice tissues. These results provide a direct mechanism for mTORC1 regulation by Leu metabolism.
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Citations
Cites
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
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941
The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
Sancak, Y., Peterson, T. R., Shaul, Y. D., Lindquist, R. A., Thoreen, C. C., Bar-Peled, L., & Sabatini, D. M. (2008) · Science · doi:10.1126/science.1157535 · Cited by 2,773
Sancak, 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 2×
“The Ragulator complex, which is encoded by theMAPKSP1, ROBLD3, and c11orf59 genes (Sancak et al., 2010), interacts with the Rag GTPases, recruits them to lysosomes, and is essential for mTORC1 activation (Sancak et al.”
Sestrin2 is a leucine sensor for the mTORC1 pathway
Wolfson, R. L., Chantranupong, L., Saxton, R. A., Shen, K., Scaria, S. M., Cantor, J. R., & Sabatini, D. M. (2016) · Science · doi:10.1126/science.aab2674 · Cited by 1,306
Amino acid signalling upstream of mTOR
Jewell, J. L., Russell, R. C., & Guan, K.-L. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3522 · Cited by 894
Regulation of autophagy by cytosolic acetyl-coenzyme A
Mariño, G., Pietrocola, F., Eisenberg, T., Kong, Y., Malik, S. A., Andryushkova, A., Schroeder, S., Pendl, T., Harger, A., Niso-Santano, M., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.01.016 · Cited by 500
Chantranupong, L., Wolfson, R. L., Orozco, J. M., Saxton, R. A., Scaria, S. M., Bar-Peled, L., Spooner, E., Isasa, M., Gygi, S. P., & Sabatini, D. M. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.014 · Cited by 466
Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway
Saxton, R. A., Knockenhauer, K. E., Wolfson, R. L., Chantranupong, L., Pacold, M. E., Wang, T., Schwartz, T. U., & Sabatini, D. M. (2016) · Science · doi:10.1126/science.aad2087 · Cited by 457
Amino acids and mTORC1: from lysosomes to disease
Efeyan, A., Zoncu, R., & Sabatini, D. M. (2012) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2012.05.007 · Cited by 436 · cited 1×
“Activation of the mTORC1 pathway by AAs correlates with the translocation of mTORC1 from undefined locations to lysosomes where it encounters RHEB, a potent mTORC1 activator (Efeyan et al., 2012; Sancak et al., 2008).”
Cited by
Modulation of cellular processes by histone and non-histone protein acetylation
Shvedunova, M., & Akhtar, A. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00441-y · Cited by 936
AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control
González, A., Hall, M. N., Lin, S.-C., & Hardie, D. G. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.01.015 · Cited by 797
Lieu, E. L., Nguyen, T., Rhyne, S., & Kim, J. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0375-3 · Cited by 818
Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases
Nixon, R. A., & Rubinsztein, D. C. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00757-5 · Cited by 435
Self-citationAmino acid-dependent control of mTORC1 signaling: a variety of regulatory modes
Takahara, T., Amemiya, Y., Sugiyama, R., Maki, M., & Shibata, H. (2020) · Journal of Biomedical Science · doi:10.1186/s12929-020-00679-2 · Cited by 300
Metadata
- Authors
- Son, S. M., Park, S. J., Lee, H., Siddiqi, F., Lee, J. E., Menzies, F. M., & Rubinsztein, D. C.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 29
- Issue
- 1
- Pages
- 192-201.e7
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2890973101
- Cited by
- 242
- References
- 10
- FWCI
- 7.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Son, S. M., Park, S. J., Lee, H., Siddiqi, F., Lee, J. E., Menzies, F. M., & Rubinsztein, D. C. (2019). Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A. Cell Metabolism. https://doi.org/10.1016/j.cmet.2018.08.013
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