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

• DOI: 10.1101/2021.09.14.460103
• Publication Date: 2021-09-16T05:30:15Z
• Authors: 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. Santos; Cher Shen Kiar; Subhankar Mukhopa...; Will M. Rae; Gordon J. Dougan; John Grainger; Paul J. Lehner; Michael Calderwood; Jyoti Choudhary; Simon Clare; Anneliese Speak; Giorgia Santilli; Alex Bateman; Kenneth G. C. Smith; Francesca Magnani; David C. Thomas
• Keywords: Phagocyte; Chronic Granulomatous Disease

Abstract EROS (Essential for Reactive Oxygen Species) protein is indispensable expression of gp91 phox , the catalytic core phagocyte NADPH oxidase. deficiency in humans a novel cause severe immunodeficiency, chronic granulomatous disease (CGD), but its mechanism action was unknown until now. We elucidate role EROS, showing it acts at earliest stages maturation. It binds immature 58kDa directly, preventing degradation and allowing glycosylation via oligosaccharyltransferase (OST) machinery incorporation heme prosthetic groups essential catalysis. also regulates purine receptors P2X7 P2X1 through direct interactions almost absent deficient mouse human primary cells. Accordingly, lack results markedly abnormal signalling, inflammasome activation T cell responses. The loss both ROS signalling leads to resistance influenza infection. Our work identifies as highly selective chaperone key proteins innate adaptive immunity rheostat has profound implications our understanding immune physiology, dysregulation possibly gene therapy.