Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation

  1. Gaojian Lian
  2. JN Rashida Gnanaprakasam
  3. Tingting Wang
  4. Ruohan Wu
  5. Xuyong Chen
  6. Lingling Liu
  7. Yuqing Shen
  8. Mao Yang
  9. Jun Yang
  10. Ying Chen
  11. Vasilis Vasiliou
  12. Teresa A Cassel
  13. Douglas R Green
  14. Yusen Liu
  15. Teresa Fan
  16. Ruoning Wang  Is a corresponding author
  1. The Research Institute at Nationwide Children's Hospital, United States
  2. St Jude Children's Research Hospital, United States
  3. Yale School of Public Health, Yale University, United States
  4. University of Kentucky, United States

Abstract

Upon antigen stimulation, T lymphocytes undergo dramatic changes in metabolism to fulfill the bioenergetic, biosynthetic and redox demands of proliferation and differentiation. Glutathione (GSH) plays an essential role in controlling redox balance and cell fate. While GSH can be recycled from Glutathione disulfide (GSSG), the inhibition of this recycling pathway does not impact GSH content and murine T cell fate. By contrast, the inhibition of the de novo synthesis of GSH, by deleting either the catalytic (Gclc) or the modifier (Gclm) subunit of glutamate-cysteine ligase (Gcl), dampens intracellular GSH, increases ROS, and impact T cell differentiation. Moreover, the inhibition of GSH de novo synthesis dampened the pathological progression of experimental autoimmune encephalomyelitis (EAE). We further reveal that glutamine provides essential precursors for GSH biosynthesis. Our findings suggest that glutamine catabolism fuels de novo synthesis of GSH and directs the lineage choice in T cells.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Gaojian Lian

    Center for Childhood Cancer and Blood Disease, The Research Institute at Nationwide Children's Hospital, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. JN Rashida Gnanaprakasam

    Center for Childhood Cancer and Blood Disease, The Research Institute at Nationwide Children's Hospital, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Tingting Wang

    Center for Childhood Cancer and Blood Disease, The Research Institute at Nationwide Children's Hospital, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ruohan Wu

    Center for Childhood Cancer and Blood Disease, The Research Institute at Nationwide Children's Hospital, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xuyong Chen

    Center for Childhood Cancer and Blood Disease, The Research Institute at Nationwide Children's Hospital, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Lingling Liu

    Center for Childhood Cancer and Blood Disease, The Research Institute at Nationwide Children's Hospital, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yuqing Shen

    Center for Childhood Cancer and Blood Disease, The Research Institute at Nationwide Children's Hospital, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Mao Yang

    Department of Immunology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jun Yang

    Department of Surgery, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Ying Chen

    Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Vasilis Vasiliou

    Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Teresa A Cassel

    Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Douglas R Green

    Department of Immunology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Yusen Liu

    Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Teresa Fan

    Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Ruoning Wang

    Center for Childhood Cancer and Blood Disease, The Research Institute at Nationwide Children's Hospital, Columbus, United States
    For correspondence
    ruoning.wang@nationwidechildrens.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9798-8032

Funding

National Institutes of Health (R21AI117547)

  • Ruoning Wang

American Cancer Society (128436-RSG-15-180-01-LIB)

  • Ruoning Wang

National Institutes of Health (1R01AI114581)

  • Ruoning Wang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal protocols were approved by the Institutional Animal Care and Use Committee of the Research Institute at Nationwide Children's Hospital (AR13-00055)

Reviewing Editor

  1. Michael L Dustin, University of Oxford, United Kingdom

Publication history

  1. Received: February 23, 2018
  2. Accepted: September 9, 2018
  3. Accepted Manuscript published: September 10, 2018 (version 1)
  4. Version of Record published: September 24, 2018 (version 2)

Copyright

© 2018, Lian 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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  1. Gaojian Lian
  2. JN Rashida Gnanaprakasam
  3. Tingting Wang
  4. Ruohan Wu
  5. Xuyong Chen
  6. Lingling Liu
  7. Yuqing Shen
  8. Mao Yang
  9. Jun Yang
  10. Ying Chen
  11. Vasilis Vasiliou
  12. Teresa A Cassel
  13. Douglas R Green
  14. Yusen Liu
  15. Teresa Fan
  16. Ruoning Wang
(2018)
Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation
eLife 7:e36158.
https://doi.org/10.7554/eLife.36158

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