p40phox: Composition, Function and Consequences of Its Absence

The NOX2 protein complex in human leukocytes consists of five proteins: gp91phox (NOX2) and p22phox (together called flavocytochrome b558) embedded in membranes, and p47phox, p67phox and p40phox in the cytosol. During cell activation (e.g. during phagocytosis of bacteria or fungi) the cytosolic components move to the membranes and form a complex with the flavocytochrome. This complex formation initiates the enzymatic activity of NOX2, i.e. accepting electrons from NADPH in the cytosol and transporting these to molecular oxygen on the apical side of the membrane, thus generating superoxide (O2–). This process is essential for killing pathogens. P40phox has a special function in this process: it directs the NOX2 complex to the membranes of phagosomes, the vacuoles that contain ingested microorganisms, thus ensuring superoxide formation in close vicinity to the pathogenic targets. Individuals with mutations in one of the genes that encode the NOX2 components suffer from a disease called chronic granulomatous disease (CGD). In general, these patients suffer from recurrent life-threatening infections with bacteria and fungi. However, patients with mutations in NCF4, encoding p40phox, rarely present with infections but instead with autoimmune and hyperinflammatory symptoms. The explanation may lie in disturbed suppression of autoreactivity against RNA antigens in B cells.