Figure 8

Model of p40/p47/p67phox membrane translocation and potential roles for the actin cytoskeleton and actin-regulatory proteins in NADPH oxidase assembly and function. At rest the p40/p47/p67phox complex is tethered to F-actin either directly or indirectly through for example moesin (bottom). Following cell activation p40phox and p47phox are activated by phosphorylation to acquire phosphoinositide and cyt b₅₅₈-binding properties (green curved arrows) and loss of tight binding to F-actin. In addition, phosphorylation may lead to binding of actin-associated proteins or adaptors like TRAF4 to the phox protein complex. This membrane recruitment part of the cycle is supported by actin depolymerization (F- to G-actin conversion). At the membrane p47phox bind cortical actin, phosphoinositides in the membrane and cyt b₅₅₈ to position p67phox for catalysis of electron transfer to cyt b₅₅₈. The specific role of actin-associated proteins in the recruitment, retention, or dissociation of p40/p47/p67phox at the membrane is unclear but WAVE1, moesin, and cortactin are likely candidates as recruiter proteins. Once the NADPH oxidase holo-enzyme has been assembled the magnitude and duration of NADPH oxidase activity is augmented by polymerization of actin (G- to F-actin conversion). Note, that cyt b₅₅₈ itself is tightly associated with cortical actin and can be redistributed through the action of IQGAP. Evidence for the role of actin in disassembly of NADPH oxidase and deactivation of p40/p47/p67phox is unavailable, but likely p40/p47/p67phox returns to a tethered state with F-actin as end-point following dephosphorylation of p47phox.