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 gp91phox/Nox2 and p22phox. The oxidase activation requires the small GTPase Rac and the SH3 domain-containing proteins p47phox and p67phox; they normally exist in the cytoplasm and translocate upon cell stimulation to the membrane. The translocation depends on a stimulus-induced conformational change of p47phox, which leads to the SH3 domain-mediated interaction with p22phox, a binding required for the gp91phox/Nox2-dependent superoxide production. Activation of Nox1, an oxidase that is likely involved in host defence at the colon, requires novel proteins homologous to p47phox and p67phox, 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 p47phox, Noxo1 seems to normally associate with p22phox, 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.
Sumimoto
Hideki
H
Medical Institute of Bioregulation, Kyushu Univerisity, Fukuoka, Japan. hsumi@bioreg.kyushy-u.ac.jp
Ueno
Noriko
N
Yamasaki
Tomoko
T
Taura
Masahiko
M
Takeya
Ryu
R
D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D019255:NADPH Oxidases / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
D013481:Superoxides; D019255:NADPH Oxidases