![]() ![]() This multi-subunit protein complex consists of (i) a membrane-bound heterodimer, gp91 phox-p22 phox, and (ii) the cytosolic components p67 phox ( Volpp et al., 1988 Nunoi et al., 1988), p47 phox ( Volpp et al., 1988 Segal et al., 1985), p40 phox ( Wientjes et al., 1993), and either Rac1 ( Abo et al., 1991) or Rac2 ( Knaus et al., 1991). The phagocyte nicotinamide adenine dinucleotide phosphate (NADPH oxidase) generates reactive oxygen species (ROS) for host defence and is a critical component of innate immunity. ![]() It has profound implications for our understanding of immune physiology, ROS dysregulation, and possibly gene therapy. ![]() Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection in mice. Accordingly, lack of murine EROS results in markedly abnormal P2X7 signalling, inflammasome activation, and T cell responses. 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. It binds the immature 58 kDa gp91 phox directly, preventing gp91 phox degradation and allowing glycosylation via the oligosaccharyltransferase machinery and the incorporation of the heme prosthetic groups essential for catalysis. We elucidate the role of EROS, showing it acts at the earliest stages of gp91 phox maturation. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease, but its mechanism of action was unknown until now. Department of Biology and Biotechnology, University of Pavia, Italy ĮROS (essential for reactive oxygen species) protein is indispensable for expression of gp91 phox, the catalytic core of the phagocyte NADPH oxidase.European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, United Kingdom. ![]() Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom.Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, United Kingdom.School of Cardiovascular Medicine and Sciences, James Black Centre, King's College London, United Kingdom.Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.Cambridge Institute of Therapeutic Immunology & Infectious Disease, Jeffrey Cheah Biomedical Centre Cambridge Biomedical Campus, United Kingdom.Cambridge Institute of Medical Research, University of Cambridge, United Kingdom.Wellcome Trust Sanger Institute, United Kingdom.Department of Cancer Biology, Dana-Farber Cancer Institute, United States.Department of Genetics, Blavatnik Institute, Harvard Medical School, United States.Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, United States.Functional Proteomics, Division of Cancer Biology, Institute of Cancer Research, United Kingdom.Molecular Immunology Unit, UCL Great Ormond Street Institute of Child Health, United Kingdom.The Department of Medicine, University of Cambridge School of Clinical Medicine, United Kingdom.Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College London, United Kingdom. ![]()
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