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

Lyra O. Randzavola, Paige M. Mortimer, Emma Garside, Elizabeth R. Dufficy, Andrea Schejtman, Georgia Roumelioti, Lu Yu, Mercedes Pardo, Kerstin Spirohn, Charlotte Tolley, Cordelia Brandt, Katherine Harcourt, Esme Nichols, Mike Nahorski, Geoff Woods, James C. Williamson, Shreehari Suresh, John M. Sowerby, Misaki Matsumoto, Celio X.C. SantosCher Shen Kiar, Subhankar Mukhopadhyay, William M. Rae, Gordon J. Dougan, John Grainger, Paul J. Lehner, Michael A. Calderwood, Jyoti Choudhary, Simon Clare, Anneliese Speak, Giorgia Santilli, Alex Bateman, Kenneth G.C. Smith, Francesca Magnani, David C. Thomas

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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, 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 58 kDa gp91phox directly, preventing gp91phox degradation and allowing glycosylation via the oligosaccharyltransferase 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.

Original languageEnglish
JournaleLife
Volume11
DOIs
Publication statusPublished - 24 Nov 2022

Keywords

  • chaperone;
  • immunology
  • inflammasome
  • inflammation
  • mouse
  • NADPH oxidase;
  • OST complex
  • P2X receptor
  • T cells

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