4/27/2023 0 Comments Destiny chaperone reviewPolymorphisms in the genes encoding subunits are also implicated in numerous autoimmune diseases ( Magnani et al., 2014). Conversely, excess ROS generation can be damaging to tissues via, for example, lipid peroxidation and have been implicated in the pathogenesis of autoimmunity ( Choi et al., 2015 Hartung et al., 1988 Noubade et al., 2014). The importance of the phagocyte NADPH oxidase is underlined by chronic granulomatous disease (CGD), a severe monogenic immunodeficiency caused by loss of individual components, which presents as susceptibility to infections with catalase-positive organisms (including Staphylococcus aureus, Salmonella, and Burkholderia species) but also with autoinflammatory manifestations, characterised by sterile granulomatous inflammation ( Alimchandani et al., 2013 Salvator et al., 2015 Goldblatt et al., 1999). Moreover, oxidation of key cysteine residues driven by H 2O 2 has been implicated in regulating other immune pathways such as inflammasome activation ( Meissner et al., 2010), type 1 interferon production ( Holmdahl et al., 2016 Sareila et al., 2017 Olsson et al., 2017 Zhong et al., 2018), LC3-associated phagocytosis ( Martinez et al., 2015 Martinez et al., 2016) and autophagy ( Thomas, 2018a, deLuca et al., 2014). Various chemical reactions then drive the production of further antimicrobial ROS such as hydrogen peroxide (H 2O 2) and hypochlorous acid. When activated by microbial stimuli, the complex facilitates the transfer of electrons from cytosolic NADPH through the gp91 phox (Nox2) protein to molecular oxygen, located either extracellularly or within phagosomes ( Segal, 2005 Thomas, 2017a), generating superoxide anions. 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. EROS (essential for reactive oxygen species) protein is indispensable for expression of gp91 phox, the catalytic core of the phagocyte NADPH oxidase.
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