Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity
- Newcastle University, United Kingdom
- Massachusetts Institute of Technology, United States
- The Beatson Institute for Cancer Research, United Kingdom
- Cardiff University, United Kingdom
- University of Birmingham, United Kingdom
Abstract
The mammalian target of rapamycin complex 1 (mTORC1) is the key signalling hub that regulates cellular protein homeostasis, growth and proliferation. Herein, we demonstrate that amino acid arginine acts independent of its metabolism to allow maximal activation of mTORC1 by growth factors, via a mechanism that does not involve regulation of mTORC1 localization to lysosomes. Instead, arginine specifically suppresses lysosomal localization of the TSC complex and interaction with its target small GTPase protein, Rheb. By interfering with TSC-Rheb complex, arginine relieves allosteric inhibition of Rheb by TSC. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signalling.
Article and author information
Author details
Reviewing Editor
- Noboru Mizushima, The University of Tokyo, Japan
Version history
- Received: August 21, 2015
- Accepted: December 30, 2015
- Accepted Manuscript published: January 7, 2016 (version 1)
- Version of Record published: February 10, 2016 (version 2)
- Version of Record updated: December 16, 2020 (version 3)
Copyright
© 2016, Carroll et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity
eLife 5:e11058.
https://doi.org/10.7554/eLife.11058
Further reading
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- Cell Biology
- Neuroscience
Mutations in Drosophila Swiss cheese (SWS) gene or its vertebrate orthologue neuropathy target esterase (NTE) lead to progressive neuronal degeneration in flies and humans. Despite its enzymatic function as a phospholipase is well established, the molecular mechanism responsible for maintaining nervous system integrity remains unclear. In this study, we found that NTE/SWS is present in surface glia that forms the blood-brain barrier (BBB) and that NTE/SWS is important to maintain its structure and permeability. Importantly, BBB glia-specific expression of Drosophila NTE/SWS or human NTE in the sws mutant background fully rescues surface glial organization and partially restores BBB integrity, suggesting a conserved function of NTE/SWS. Interestingly, sws mutant glia showed abnormal organization of plasma membrane domains and tight junction rafts accompanied by the accumulation of lipid droplets, lysosomes, and multilamellar bodies. Since the observed cellular phenotypes closely resemble the characteristics described in a group of metabolic disorders known as lysosomal storage diseases (LSDs), our data established a novel connection between NTE/SWS and these conditions. We found that mutants with defective BBB exhibit elevated levels of fatty acids, which are precursors of eicosanoids and are involved in the inflammatory response. Also, as a consequence of a permeable BBB, several innate immunity factors are upregulated in an age-dependent manner, while BBB glia-specific expression of NTE/SWS normalizes inflammatory response. Treatment with anti-inflammatory agents prevents the abnormal architecture of the BBB, suggesting that inflammation contributes to the maintenance of a healthy brain barrier. Considering the link between a malfunctioning BBB and various neurodegenerative diseases, gaining a deeper understanding of the molecular mechanisms causing inflammation due to a defective BBB could help to promote the use of anti-inflammatory therapies for age-related neurodegeneration.
