Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte β- selection

  1. Xia Liu
  2. Jingjing Yu
  3. Longyong Xu
  4. Katharine Umphred-Wilson
  5. Fanglue Peng
  6. Yao Ding
  7. Brendan M Barton
  8. Xiangdong Lv
  9. Michael Y Zhao
  10. Shengyi Sun
  11. Yuning Hong
  12. Ling Qi
  13. Stanley Adoro  Is a corresponding author
  14. Xi Chen  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. Case Western Reserve University, United States
  3. Wayne State University, United States
  4. La Trobe University, Australia
  5. University of Michigan-Ann Arbor, United States

Abstract

Signals from the pre-T cell receptor and Notch coordinately instruct b-selection of CD4-CD8- double negative (DN) thymocytes to generate ab T cells in the thymus. However, how these signals ensure a high-fidelity proteome and safeguard the clonal diversification of the pre-selection TCR repertoire given the considerable translational activity imposed by b-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint during b-selection. Expression of the SEL1L-HRD1 complex, the most conserved branch of ERAD, is directly regulated by the transcriptional activity of the Notch intracellular domain. Deletion of Sel1l impaired DN3 to DN4 thymocyte transition and severely impaired mouse ab T cell development. Mechanistically, Sel1l deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. Accordingly, genetically inactivating PERK rescued T cell development from Sel1l-deficient thymocytes. In contrast, IRE1a/XBP1 pathway was induced as a compensatory adaptation to alleviate Sel1l-deficiency induced ER stress. Dual loss of Sel1l and Xbp1 markedly exacerbated the thymic defect. Our study reveals a critical developmental signal controlled proteostasis mechanism that enforces T cell development to ensure a healthy adaptive immunity.

Data availability

Sequencing data have been deposited in GEO under accession code GSE173993.All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all Figures.

The following data sets were generated

Article and author information

Author details

  1. Xia Liu

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jingjing Yu

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Longyong Xu

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Katharine Umphred-Wilson

    Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6416-0466
  5. Fanglue Peng

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yao Ding

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Brendan M Barton

    Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Xiangdong Lv

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Michael Y Zhao

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Shengyi Sun

    Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Yuning Hong

    Department of Chemistry and Physics, La Trobe University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Ling Qi

    Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Stanley Adoro

    Case Western Reserve University, Cleveland, United States
    For correspondence
    sxa726@case.edu
    Competing interests
    The authors declare that no competing interests exist.
  14. Xi Chen

    Baylor College of Medicine, Houston, United States
    For correspondence
    xi.chen@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7995-6202

Funding

National Heart, Lung, and Blood Institute (R01HL146642)

  • Xi Chen

Cancer Prevention and Research Institute of Texas (RP160283)

  • Fanglue Peng

National Institute of Allergy and Infectious Diseases (R01 AI1143992)

  • Stanley Adoro

National Cancer Institute (R37CA228304)

  • Xi Chen

National Cancer Institute (K22CA218467)

  • Stanley Adoro

National Cancer Institute (P50CA186784)

  • Xi Chen

National Institute of General Medical Sciences (R35GM130292)

  • Ling Qi

DOD Peer Reviewed Cancer Research Program (W81XWH1910524)

  • Xi Chen

DOD Peer Reviewed Cancer Research Program (W81XWH1910306)

  • Stanley Adoro

Congressionally Directed Medical Research Programs (W81XWH1910035)

  • Xiangdong Lv

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

Ethics

Animal experimentation: All protocols described in this study were approved by the Baylor College of Medicine Institutional Animal Care and Use Committee (protocol: AN-6813) or Case Western Reserve University Institutional Animal Care and Use Committee (protocol: 2017-0055).

Reviewing Editor

  1. Juan Carlos Zúñiga-Pflücker, University of Toronto, Sunnybrook Research Institute, Canada

Version history

  1. Received: May 3, 2021
  2. Preprint posted: May 7, 2021 (view preprint)
  3. Accepted: July 5, 2021
  4. Accepted Manuscript published: July 9, 2021 (version 1)
  5. Version of Record published: July 27, 2021 (version 2)
  6. Version of Record updated: July 28, 2021 (version 3)

Copyright

© 2021, Liu 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. Xia Liu
  2. Jingjing Yu
  3. Longyong Xu
  4. Katharine Umphred-Wilson
  5. Fanglue Peng
  6. Yao Ding
  7. Brendan M Barton
  8. Xiangdong Lv
  9. Michael Y Zhao
  10. Shengyi Sun
  11. Yuning Hong
  12. Ling Qi
  13. Stanley Adoro
  14. Xi Chen
(2021)
Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte β- selection
eLife 10:e69975.
https://doi.org/10.7554/eLife.69975

Share this article

https://doi.org/10.7554/eLife.69975

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