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


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.

SUBMITTER: Randzavola LO 

PROVIDER: S-EPMC9767466 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Randzavola Lyra O LO   Mortimer Paige M PM   Garside Emma E   Dufficy Elizabeth R ER   Schejtman Andrea A   Roumelioti Georgia G   Yu Lu L   Pardo Mercedes M   Spirohn Kerstin K   Tolley Charlotte C   Brandt Cordelia C   Harcourt Katherine K   Nichols Esme E   Nahorski Mike M   Woods Geoff G   Williamson James C JC   Suresh Shreehari S   Sowerby John M JM   Matsumoto Misaki M   Santos Celio X C CXC   Kiar Cher Shen CS   Mukhopadhyay Subhankar S   Rae William M WM   Dougan Gordon J GJ   Grainger John J   Lehner Paul J PJ   Calderwood Michael A MA   Choudhary Jyoti J   Clare Simon S   Speak Anneliese A   Santilli Giorgia G   Bateman Alex A   Smith Kenneth G C KGC   Magnani Francesca F   Thomas David C DC  

eLife 20221124


EROS (essential for reactive oxygen species) protein is indispensable for expression of gp91<i>phox</i>, 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 gp91<i>phox</i> maturation. It binds the immature 58 kDa gp91<i>phox</i> directly, preventing gp91<i>phox</i> degr  ...[more]

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