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 phox maturation.
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. 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. They convincingly demonstrate how EROS is involved in the maturation of gp91phox and expand our knowledge of the role of EROS in regulating the expression of the P2x7 ion channel.
This work will be of interest to biochemists and immunologists. The phagocyte nicotinamide adenine dinucleotide phosphate NADPH oxidase generates reactive oxygen species ROS for host defence and is a critical component of innate immunity. 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.
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, ; Thomas, a , generating superoxide anions.
