EROS is a selective chaperone regulating the phagocyte NADPH oxidase and purinergic signalling

  1. Lyra O Randzavola
  2. Paige M Mortimer
  3. Emma Garside
  4. Elisabeth R Dufficy
  5. Andrea Schejtman
  6. Georgia Roumelioti
  7. Lu Yu
  8. Mercedes Pardo
  9. Kerstin Spirohn
  10. Charlotte Tolley
  11. Cordelia Brandt
  12. Katherine Harcourt
  13. Esme Nichols
  14. Mike Nahorski
  15. Geoff Woods
  16. James C Williamson
  17. Shreehari Suresh
  18. John M Sowerby
  19. Misaki Matsumoto
  20. Celio XC Santos
  21. Cher Shen Kiar
  22. Subhankar Mukhopadhyay
  23. Will M Rae
  24. Gordon J Dougan
  25. John Grainger
  26. Paul J Lehner
  27. Michael A Calderwood
  28. Jyoti Choudhary
  29. Simon Clare
  30. Anneliese Speak
  31. Giorgia Santilli
  32. Alex Bateman
  33. Kenneth GC Smith
  34. Francesca Magnani  Is a corresponding author
  35. David C Thomas  Is a corresponding author
  1. Imperial College London, United Kingdom
  2. University of Cambridge, United Kingdom
  3. University College London, United Kingdom
  4. Institute of Cancer Research, United Kingdom
  5. Dana-Farber Cancer Institute, United States
  6. Wellcome Sanger Institute, United Kingdom
  7. Kyoto Prefectural University of Medicine, Japan
  8. King's College London, United Kingdom
  9. University of Manchester, United Kingdom
  10. Harvard University, United States
  11. European Molecular Biology Laboratory, United Kingdom
  12. University of Pavia, Italy

Abstract

EROS (Essential for Reactive Oxygen Species) protein is indispensable for expression of gp91phox, the catalytic core of the phagocyte NADPH oxidase. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease (CGD), but its mechanism of action was unknown until now. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58kDa gp91phox directly, preventing gp91phox degradation and allowing glycosylation via the oligosaccharyltransferase (OST) machinery and the incorporation of the heme prosthetic groups essential for catalysis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions and P2X7 is almost absent in EROS deficient mouse and human primary cells. Accordingly, lack of murine EROS results in markedly abnormal P2X7 signalling, inflammasome activation and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection in mice. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, ROS dysregulation and possibly gene therapy.

Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier "PXD024659". The plasma membrane profiling mass spectrometry data has the identifier "PXD025149".

The following data sets were generated

Article and author information

Author details

  1. Lyra O Randzavola

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Paige M Mortimer

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Emma Garside

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Elisabeth R Dufficy

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Andrea Schejtman

    Molecular Immunology Unit, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Georgia Roumelioti

    Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Lu Yu

    Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Mercedes Pardo

    Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Kerstin Spirohn

    Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Charlotte Tolley

    Wellcome Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Cordelia Brandt

    Wellcome Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Katherine Harcourt

    Wellcome Sanger Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Esme Nichols

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Mike Nahorski

    Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Geoff Woods

    Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. James C Williamson

    Cambridge Institute for Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Shreehari Suresh

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  18. John M Sowerby

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  19. Misaki Matsumoto

    Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto, Japan
    Competing interests
    The authors declare that no competing interests exist.
  20. Celio XC Santos

    School of Cardiovascular Medicine and Sciences, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  21. Cher Shen Kiar

    Peter Gorer Department of Immunobiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  22. Subhankar Mukhopadhyay

    Peter Gorer Department of Immunobiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  23. Will M Rae

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  24. Gordon J Dougan

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  25. John Grainger

    Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  26. Paul J Lehner

    Cambridge Institute for Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9383-1054
  27. Michael A Calderwood

    Department of Genetics, Harvard University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  28. Jyoti Choudhary

    Division of Cancer Biol, Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  29. Simon Clare

    Wellcome Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  30. Anneliese Speak

    Wellcome Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  31. Giorgia Santilli

    Molecular Immunology Unit, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  32. Alex Bateman

    European Bioinformatics Institute, European Molecular Biology Laboratory, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6982-4660
  33. Kenneth GC Smith

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  34. Francesca Magnani

    Department of Biology and Biotechnology, University of Pavia, Italy, Italy
    For correspondence
    francesca.magnani@unipv.it
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0812-9397
  35. David C Thomas

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    For correspondence
    david.thomas1@imperial.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9738-2329

Funding

Wellcome Trust (098051)

  • David C Thomas

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

Ethics

Animal experimentation: The care and use of all mice were in accordance with UK Home Office regulations (UK Animals Scientific Procedures Act 1986)

Reviewing Editor

  1. Simon Yona, The Hebrew University of Jerusalem, Israel

Publication history

  1. Received: December 15, 2021
  2. Accepted: October 31, 2022
  3. Accepted Manuscript published: November 24, 2022 (version 1)

Copyright

© 2022, Randzavola 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. Lyra O Randzavola
  2. Paige M Mortimer
  3. Emma Garside
  4. Elisabeth R Dufficy
  5. Andrea Schejtman
  6. Georgia Roumelioti
  7. Lu Yu
  8. Mercedes Pardo
  9. Kerstin Spirohn
  10. Charlotte Tolley
  11. Cordelia Brandt
  12. Katherine Harcourt
  13. Esme Nichols
  14. Mike Nahorski
  15. Geoff Woods
  16. James C Williamson
  17. Shreehari Suresh
  18. John M Sowerby
  19. Misaki Matsumoto
  20. Celio XC Santos
  21. Cher Shen Kiar
  22. Subhankar Mukhopadhyay
  23. Will M Rae
  24. Gordon J Dougan
  25. John Grainger
  26. Paul J Lehner
  27. Michael A Calderwood
  28. Jyoti Choudhary
  29. Simon Clare
  30. Anneliese Speak
  31. Giorgia Santilli
  32. Alex Bateman
  33. Kenneth GC Smith
  34. Francesca Magnani
  35. David C Thomas
(2022)
EROS is a selective chaperone regulating the phagocyte NADPH oxidase and purinergic signalling
eLife 11:e76387.
https://doi.org/10.7554/eLife.76387

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