Molecular mechanism underlying activation of superoxide-producing NADPH oxidases: Roles for their regulatory proteins

The phagocyte NADPH oxidase is dormant in resting cells but becomes activated during phagocytosis to produce superoxide, a precursor of microbicidal oxidants, thereby playing a crucial role in host defence. The catalytic core of this enzyme comprises the two membranous subunits gp91^phox/Nox2 and p22^phox. The oxidase activation requires the small GTPase Rae and the SH3 domain-containing proteins p47^phox and p67^phox, they normally exist in the cytoplasm and translocate upon cell stimulation to the membrane. The translocation depends on a stimulus-induced conformational change of p47^phox, which leads to the SH3 domain-mediated interaction with p22^phox, a binding required for the gp96^phox /Nox2-dependent super-oxide production. Activation of Nox1, an oxidase that is likely involved in host defence at the colon, requires novel proteins homologous to p47^phox and p67^phox, designated Noxo1 and Noxa1, respectively. Noxo1 and Noxa1, both expressed abundantly in the colon, are capable of constitutively activating Nox1. The constitutive activation may be due to the property of Noxo1: in contrast with p47^phox, Noxo1 seems to normally associate with p22^phox, which is required for the Nox1 activation. We will also describe the mechanism underlying regulation of the third oxidase Nox3, which exits in fetal kidney and inner ears.