Biological Roles for the NOX Family NADPH Oxidases

Abstract

Linking the phagocyte defect in patients with chronic granulomatous disease (CGD) 2 with the biochemical basis for oxygen consumption by stimulated neutrophils (1) represented a seminal advance in understanding the molecular basis for a key component of innate immunity. In subsequent decades, the catalytic and regulatory elements of the "respiratory burst oxidase" were elucidated, tacitly assuming all along that the NADPH-dependent oxidase under study represented a system uniquely expressed in phagocytic cells and dedicated to generating relatively large amounts of reactive oxygen species (ROS) destined to destroy invading microbes. Development of more sensitive analytical systems for ROS detection revealed that some physiological and pathophysiological events in non-phagocytic cells were associated with ROS generation, although the subcellular source of oxidants remained uncertain. With the identification of mox1 in 1999 (2) as a homolog of gp91 phox , the catalytic component of the phagocyte oxidase, came the birth of the NADPH oxidase (NOX) protein family and the eventual identification of its seven members. With remarkable rapidity, many features of the structure, activity, cell biology, and physiology of the NOX proteins have been described, as summarized in several excellent and comprehensive recent reviews (3)(4)(5). This more circumscribed minireview provides an overview of the organizing features of the protein family, a summary of the physiology and pathophysiology in which NOX proteins participate (or might participate), and identification of some of the remaining unanswered questions in the field.

Role of Rac GTPase activating proteins in regulation of NADPH oxidase in human neutrophils

“…Defective function of some of these proteins leads to serious pathologic conditions in humans [8,9]. However, numerous reports show that inappropriate activation of Nox proteins results in serious damage, mainly in the cardiovascular system [7,10]. Thus, strict spatiotemporal control of the activity of Nox family proteins is vitally important.…”

Yno1p/Aim14p, a NADPH-oxidase ortholog, controls extramitochondrial reactive oxygen species generation, apoptosis, and actin cable formation in yeast

“…5). Whereas the human NOX2 was discovered early on, other NOX (Nox1/3/4/5) as well as dual oxidase (DUOX) (Duox1/2) enzymes (displaying two domains: a NADPH oxidase domain and a peroxidase domain) have been found relatively recently in human cells.…”

“…On the one hand, xanthine oxidase, an enzyme in the catabolism of purines, which catalyses the oxidation of hypoxanthine to xanthine and to uric acid, produces superoxide (4). On the other hand, NADPH oxidases (NOX) catalyze the production of superoxide from oxygen and NADPH (5).…”

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

“…5 There are six homologues of Nox2 (namely Nox1, Nox3, Nox4, Nox5, Duox1 and Duox2); each has a specific pattern of expression, but their specific roles remain to be unravelled. 4 A few recent reports have described the relevance of NADPH oxidase ROS production in the differentiation of different kind of cells. 6,7 Therefore, it is tempting to speculate that NADPH ROS production might be a general mechanism common to all types of cell differentiation.…”

“…The main non-mitochondrial sources of ROS are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox). 4 These proteins are membrane-associated multi-protein complexes that produce superoxide (O 2 À ). The first complex to be described was the phagocyte NADPH oxidase, which produces huge amounts of superoxide and other ROS that are crucial for host defence.…”