Les Nox/Duox : une nouvelle famille de NADPH oxydases

Abstract

La production des formes réactives de l’oxygène par la NADPH oxydase phagocytaire a été longtemps considérée comme restreinte aux phagocytes professionnels. Récemment, six homologues de la sous-unité catalytique de la NADPH oxydase phagocytaire (gp91 phox ou Nox-2) ont été identifiés et appartiennent à la famille des Nox : Nox-1, Nox-3, Nox-4, Nox-5, Duox-1 et Duox-2. Ces enzymes ont la capacité de transporter des électrons à travers la membrane plasmique et produisent de l’anion superoxyde, luimême précurseur des autres formes réactives de l’oxygène. Cependant, la distribution tissulaire et les mécanismes d’activation des membres de la famille Nox sont très différents, suggérant qu’ils exercent des fonctions physiologiques distinctes dans des mécanismes aussi variés que la défense de l’hôte, la croissance, la différenciation et l’apoptose. La modulation de la fonction des différentes Nox peut être à l’origine d’une grande variété d’événements physiopathologiques.

Reactive oxygen species (ROS) generated by the NADPH oxidases are conventionally thought to be cytotoxic and mutagenic and at high levels induce an oxidative stress response. The phagocyte NADPH oxidase catalyzes the NADPH-dependent reduction of molecular oxygen to generate superoxide O2 -·, which can dismute to generate ROS species. Together, these ROS participate in host defence by killing or damaging invading microbes. Flavocytochrome b558 is the catalytic core of the phagocyte NADPH oxidase and consists of a large glycoprotein gp91 phox or Nox-2 and a small protein p22 phox . The other components of the NADPH oxidase are cytosolic proteins, namely p67 phox , p47 phox , p40 phox and Rac. A defect in any of the genes encoding gp91 phox , p22 phox , p67 phox or p47 phox results in chronic granulomatous disease, a genetic disorder characterized by severe and recurrent infections. Evidence is rapidly accumulating that low level of ROS were produced by NADPH oxidase homologs in non-phagocytic cells. To date, six human homologs (Nox-1, Nox-3, Nox-4, Nox-5, Duox-1 and Duox-2) have been recently identified in a variety of non-phagocytic cells. The identification of Nox-1 was quickly followed by the cloning of Nox-3, Nox-4, and Nox-5. In parallel, two very large members of the Nox family were discovered, namely Duox-1 and Duox-2, initially also referred to as thyroid oxidases. The physiological functions of Nox-dependent ROS generation are in progress and still require detailed characterization. Activation mechanisms and tissue distribution of the different members of the Nox family are very different, suggesting distinct physiological functions. Nox family enzymes are likely to be involved in a variety of physiological events including cell proliferation, host defence, differentiation, apoptosis, senescence and activation of growth-related signaling pathways. An increase and a decrease in the function of Nox enzymes can contribute to a wide range of pathological processes.