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
Multicellular organisms are composed of specialized cell types with distinct proteomes. While recent advances in single-cell transcriptome analyses have revealed differential expression of mRNAs, cellular diversity in translational profiles remains underinvestigated. By performing RNA-seq and Ribo-seq in genetically defined cells in the Drosophila brain, we here revealed substantial post-transcriptional regulations that augment the cell-type distinctions at the level of protein expression. Specifically, we found that translational efficiency of proteins fundamental to neuronal functions, such as ion channels and neurotransmitter receptors, was maintained low in glia, leading to their preferential translation in neurons. Notably, distribution of ribosome footprints on these mRNAs exhibited a remarkable bias toward the 5′ leaders in glia. Using transgenic reporter strains, we provide evidence that the small upstream open-reading frames in the 5’ leader confer selective translational suppression in glia. Overall, these findings underscore the profound impact of translational regulation in shaping the proteomics for cell-type distinction and provide new insights into the molecular mechanisms driving cell-type diversity.
