Biological Roles for the NOX Family NADPH Oxidases
William M. Nauseef


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 gp91phox, 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 (3–5). 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.

FIGURE 2.
Structural organization of NOX protein family members. There are four different formats for the structural organization of members of the NOX protein family depending on the nature of their activity (constitutive versus agonist-dependent), the requirement of p22phox, dependence on cytosolic cofactors, the presence of EF-hands, and dependence on calcium. Duox alone has an additional transmembrane domain with an extracellular domain with limited sequence homology to animal peroxidases (PRX).

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