Randzavola, Lyra O;
Mortimer, Paige M;
Garside, Emma;
Dufficy, Elizabeth R;
Schejtman, Andrea;
Roumelioti, Georgia;
Yu, Lu;
... Thomas, David C; + view all
(2022)
EROS is a selective chaperone regulating the phagocyte NADPH oxidase and purinergic signalling.
eLife
, 11
, Article e76387. 10.7554/eLife.76387.
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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 dysregula-tion, and possibly gene therapy.
| Type: | Article |
|---|---|
| Title: | EROS is a selective chaperone regulating the phagocyte NADPH oxidase and purinergic signalling |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.7554/eLife.76387 |
| Publisher version: | https://doi.org/10.7554/eLife.76387 |
| Language: | English |
| Additional information: | © 2022, Randzavola, Mortimer et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biology, Life Sciences & Biomedicine - Other Topics, NADPH oxidase, chaperone, inflammasome, P2X receptor, OST complex, T cells, Mouse, CHRONIC GRANULOMATOUS-DISEASE, CYTOCHROME B(558), FLAVOCYTOCHROME B(558), RESPIRATORY BURST, RECEPTOR, PROTEIN, NEUTROPHILS, ACTIVATION, BIOSYNTHESIS, EXPRESSION |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10164629 |
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