NADPH oxidase activation in neutrophils: Role of the phosphorylation of its subunits

Abstract

Neutrophils are key cells of innate immunity and during inflammation. Upon activation, they produce large amounts of superoxide anion (O₂ ^-. ) and ensuing reactive oxygen species (ROS) to kill phagocytized microbes. The enzyme responsible for O₂ ^-. production is called the phagocyte NADPH oxidase. This is a multicomponent enzyme system that becomes active after assembly of four cytosolic proteins (p47^phox , p67^phox , p40^phox and Rac2) with the transmembrane proteins (p22^phox and gp91^phox , which form the cytochrome b₅₅₈ ). gp91^phox represents the catalytic subunit of the NADPH oxidase and is also called NOX2. NADPH oxidase-derived ROS are essential for microbial killing and innate immunity; however, excessive ROS production induces tissue injury and prolonged inflammatory reactions that contribute to inflammatory diseases. Thus, NADPH oxidase activation must be tightly regulated in time and space to limit ROS production. NADPH oxidase activation is regulated by several processes such as phosphorylation of its components, exchange of GDP/GTP on Rac2 and binding of p47^phox and p40^phox to phospholipids. This review aims to provide new insights into the role of the phosphorylation of the NADPH oxidase components, that is gp91^phox , p22^phox , p47^phox , p67^phox and p40^phox , in the activation of this enzyme.

Keywords: NADPH oxidase; NOX2; Rac2; gp91phox; neutrophils; p22phox; p47phox; p67phox and p40phox; protein phosphorylation.