1. Immunology and Inflammation
Download icon

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
Research Article
  • Cited 0
  • Views 301
  • Annotations
Cite as: eLife 2018;7:e36158 doi: 10.7554/eLife.36158

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.

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 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)

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.

Metrics

  • 301
    Page views
  • 99
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

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

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

Further reading

    1. Cancer Biology
    2. Immunology and Inflammation
    Jakob Nikolas Kather et al.
    Research Article Updated
    1. Developmental Biology
    2. Immunology and Inflammation
    Federico Andrea Moretti et al.
    Research Article