p47phox, the phagocyte NADPH oxidase/NOX2 organizer: structure, phosphorylation and implication in diseases

Abstract

Phagocytes such as neutrophils play a vital role in host defense against microbial pathogens. The anti-microbial function of neutrophils is based on the production of superoxide anion (O 2 -), which generates other microbicidal reactive oxygen species (ROS) and release of antimicrobial peptides and proteins. The enzyme responsible for O 2 -production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. NADPH oxidase activation in phagocytes can be induced by a large number of soluble and particulate agents. This process is dependent on the phosphorylation of the cytosolic protein p47phox. p47phox is a 390 amino acids protein with several functional domains: one phox homology (PX) domain, two src homology 3 (SH3) domains, an auto-inhibitory region (AIR), a proline rich domain (PRR) and has several phosphorylated sites located between Ser303 and Ser379. In this review, we will describe the structure of p47phox, its phosphorylation and discuss how these events regulate NADPH oxidase activation.

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

“…Nevertheless, the existence of a feedforward loop is also possible, that is, the assembly of the NADPH oxidase involved in differentiation might be under the control of some of the signalling pathways activated during the process, and the ensuing ROS production would have a positive effect leading to full activation of the signalling cascades. In this sense, it is important to note that NADPH oxidase complex assembly is dependent on p47 phox phosphorylation, 5 which occurs in response to several different kinases, 31 some of which are important for megakaryocytopoiesis.…”

Homocysteine-induced cardiomyocyte apoptosis and plasma membrane flip-flop are independent of S-adenosylhomocysteine: a crucial role for nuclear p47phox

“…In PMNs, gp91 phox (NOX2) is located in the plasma membrane and during activation p47 phox translocates from the cytosol to the membrane to form a complex with NOX2 [29]. For an active NOX complex to occur, both NOX2 and p47 phox have to be phosphorylated, and in neutrophils, it has already been established that NOX2 is phosphorylated by protein kinase C (PKC) [30].…”

Mechanosensitive Regulation of Cortactin by p47 phox

“…1 The prototype Nox2 comprises 2 transmembrane subunits (gp91 phox [Nox2] and p22 phox ) and 3 cytosolic subunits (p47 phox , p67 phox , and p40 phox ). 2,3 Nox2 is characteristically found in phagocytic cells, where it has a critical antimicrobial function through the production of superoxide anion.…”

“…1 In the resting state, it localizes in the cytoplasm where its activity is inhibited through an autoinhibitory phosphorylation. However, on cell stimulation, p47 phox interacts with cytosolic subunits p67 phox and p40 phox and the complex translocates to the cell membrane to assemble the active oxidase, which generates superoxide anion.…”