Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity

  1. Bernadette Carroll
  2. Dorothea Maetzel
  3. Oliver DK Maddocks
  4. Gisela Otten
  5. Matthew Ratcliff
  6. Graham R Smith
  7. Elaine A Dunlop
  8. João F Passos
  9. Owen R Davies
  10. Rudolf Jaenisch
  11. Andrew R Tee
  12. Sovan Sarkar
  13. Viktor I Korolchuk  Is a corresponding author
  1. Newcastle University, United Kingdom
  2. Massachusetts Institute of Technology, United States
  3. The Beatson Institute for Cancer Research, United Kingdom
  4. Cardiff University, United Kingdom
  5. 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

  1. Bernadette Carroll

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Dorothea Maetzel

    Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Oliver DK Maddocks

    The Beatson Institute for Cancer Research, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Gisela Otten

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Matthew Ratcliff

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Graham R Smith

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Elaine A Dunlop

    Institute of Cancer and Genetics, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. João F Passos

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Owen R Davies

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Rudolf Jaenisch

    Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Andrew R Tee

    Institute of Cancer and Genetics, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Sovan Sarkar

    Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Viktor I Korolchuk

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    For correspondence
    viktor.korolchuk@ncl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

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.

Metrics

  • 9,017
    views
  • 1,780
    downloads
  • 153
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Bernadette Carroll
  2. Dorothea Maetzel
  3. Oliver DK Maddocks
  4. Gisela Otten
  5. Matthew Ratcliff
  6. Graham R Smith
  7. Elaine A Dunlop
  8. João F Passos
  9. Owen R Davies
  10. Rudolf Jaenisch
  11. Andrew R Tee
  12. Sovan Sarkar
  13. Viktor I Korolchuk
(2016)
Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity
eLife 5:e11058.
https://doi.org/10.7554/eLife.11058

Share this article

https://doi.org/10.7554/eLife.11058

Further reading

    1. Cell Biology
    2. Genetics and Genomics
    Keva Li, Nicholas Tolman ... UK Biobank Eye and Vision Consortium
    Research Article

    A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.