Dual Role of Rac in the Assembly of NADPH Oxidase, Tethering to the Membrane and Activation of p67

Sarfstein, Rive; Gorzalczany, Yara; Mizrahi, Ariel; Berdichevsky, Yevgeny; Molshanski-Mor, Shahar; Weinbaum, Carolyn; Hirshberg, Miriam; Dagher, Marie-Claire; Pick, Edgar

doi:10.1074/jbc.m312394200

Cited by 124 publications

(151 citation statements)

References 45 publications

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“…Whereas p47 phox and p67 phox translocate to the membrane in a complex with p40 phox , Rac2 translocates in its GTP-bound form independent of p47 phox and p67 phox (22). Rac2 participates in the catalytic activity of the phagocyte oxidase directly, via its interactions with p67 phox , or both (23,24). Additional factors modulate the stability and activity of the assembled complex, although the extent of their contribution to oxidase function is incompletely understood.…”

Section: The Phagocyte Paradigmmentioning

confidence: 99%

Biological Roles for the NOX Family NADPH Oxidases

Nauseef

2008

Journal of Biological Chemistry

285

225

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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.

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Section: The Phagocyte Paradigmmentioning

confidence: 99%

Biological Roles for the NOX Family NADPH Oxidases

Nauseef

2008

Journal of Biological Chemistry

285

225

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“…Thus, activation involves an assembly of regulatory subunits with the catalytic subunit, resulting in the activation electron flow through the prosthetic groups of the catalytic subunit Nox2. [48] which may permit the activation domain of p67 phox to act on Nox2. Second, studies using a diaphorase electron acceptor to intercept electrons from the FAD support the view that Rac plays a direct role in stimulating electron transfers that is independent of p67 phox [49].…”

Section: Regulatory Subunits For the Nox2 Systemmentioning

confidence: 99%

Regulation of Nox and Duox enzymatic activity and expression

Lambeth

Kawahara

Diebold

2007

Free Radical Biology and Medicine

454

422

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SummaryIn recent years, it has become clear that reactive oxygen species (ROS, which include superoxide, hydrogen peroxide and other metabolites) are produced in biological systems. Rather than being simply a byproduct of aerobic metabolism, it is now recognized that specific enzymes ---the Nox (NADPH-oxidase) and Duox (Dual oxidase) enzymes ----seem to have the sole function of generating ROS in a carefully regulated manner, and key roles in signal transduction, immune function, hormone biosynthesis and other normal biological functions are being uncovered. The prototypical Nox is the respiratory burst oxidase or phagocyte oxidase, which generates large amounts of superoxide and other reactive species in the phagosomes of neutrophils and macrophages, playing a central role in innate immunity by killing microbes. This enzyme system has been extensively studied over the past two decades, and provides a basis for comparison with the more recently described Nox and Duox enzymes, which generate ROS in a variety of cells and tissues. This review first considers the structure and regulation of the respiratory burst oxidase, and then reviews recent studies relating to the regulation of the activity of the novel Nox/Duox enzymes. The regulation of Nox and Duox expression in tissues and by specific stimuli is also considered here. An accompanying review considers biological and pathological roles of the Nox family of enzymes. The Respiratory Burst Oxidase of Phagocytes a. The respiratory burstThe "respiratory burst" refers to the early observation that when professional phagocytes such as neutrophils and macrophages are exposed to microbes, they consume large amounts of oxygen. Unexpectedly, this oxygen consumption was not inhibited by cyanide, an inhibitor of mitochondrial electron transport. This observation led to a more than 25 year search for the enzymatic origin of the respiratory burst and to the eventual discovery and molecular characterization of the phagocytic NADPH-oxidase or "respiratory burst oxidase". The phagocyte oxidase generates superoxide via the one electron-reduction of oxygen by NADPH, with secondary production of hydrogen peroxide, HOCl and other activated forms of oxygen. Together, these reactive oxygen species (ROS) participate in host defense by killing invading microbes. b. gp91 phox , the catalytic moiety of the respiratory burst oxidaseThe phagocytic NADPH-oxidase consists of a membrane-localized glycosylated, catalytic subunit, gp91 phox (which has also come to be known as Nox2, a terminology that will be used in this review), along with a second membrane-associated subunit, p22 phox , both depicted in Fig. 1. Nox2 and p22 phox stabilize one another in a tightly associated heterodimer which is referred to as flavocytochrome b 558 . The C-terminal half of Nox2 forms a domain that is Contact information: 148 Whitehead Biomedical Research Building, Department of Pathology and Laboratory Medicine, 615 Michael Street, Atlanta, GA 30322, U.S. A. Phone: 404-727-5875, Fax: 404-712-2979, e-mail: nox...

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“…phox (35)(36)(37)(38)(39). To test the role of the p67 phox region of amino acids 190 -210 in binding to the C-terminal NADPH-binding domain of gp91 phox (amino acids 384 -570), we performed a GST pull-down assay using purified p67 phox proteins (Fig.…”

Section: Role Of the Region Of Amino Acids 190 -205 In P67mentioning

confidence: 99%

A Conserved Region between the TPR and Activation Domains of p67 Participates in Activation of the Phagocyte NADPH Oxidase

Maehara

Miyano

Yuzawa

et al. 2010

Journal of Biological Chemistry

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The phagocyte NADPH oxidase, dormant in resting cells, is activated during phagocytosis to produce superoxide, a precursor of microbicidal oxidants. The membrane-integrated protein gp91 phox serves as the catalytic core, because it contains a complete electron-transporting apparatus from NADPH to molecular oxygen for superoxide production. Activation of gp91 phox requires the cytosolic proteins p67 phox , p47 phox , and Rac (a small GTPase). p67 phox , comprising 526 amino acids, moves upon cell stimulation to the membrane together with p47 phox and there interacts with Rac; these processes are prerequisite for gp91 phox .

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Dual Role of Rac in the Assembly of NADPH Oxidase, Tethering to the Membrane and Activation of p67

Cited by 124 publications

References 45 publications

Biological Roles for the NOX Family NADPH Oxidases

Biological Roles for the NOX Family NADPH Oxidases

Regulation of Nox and Duox enzymatic activity and expression

A Conserved Region between the TPR and Activation Domains of p67 Participates in Activation of the Phagocyte NADPH Oxidase

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