EROS is a selective chaperone regulating the phagocyte NADPH oxidase and purinergic signalling
- Imperial College London, United Kingdom
- University of Cambridge, United Kingdom
- University College London, United Kingdom
- Institute of Cancer Research, United Kingdom
- Dana-Farber Cancer Institute, United States
- Wellcome Sanger Institute, United Kingdom
- Kyoto Prefectural University of Medicine, Japan
- King's College London, United Kingdom
- University of Manchester, United Kingdom
- Harvard University, United States
- European Molecular Biology Laboratory, United Kingdom
- 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".
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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)
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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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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