NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease

Abstract

Nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (NOX) is an enzyme complex with the sole function of producing superoxide anion and reactive oxygen species (ROS) at the expense of NADPH. Vital to the immune system as well as cellular signaling, NOX is also involved in the pathologies of a wide variety of disease states. Particularly, it is an integral player in many neurological diseases, including stroke, TBI, and neurodegenerative diseases. Pathologically, NOX produces an excessive amount of ROS that exceed the body’s antioxidant ability to neutralize them, leading to oxidative stress and aberrant signaling. This prevalence makes it an attractive therapeutic target and as such, NOX inhibitors have been studied and developed to counter NOX’s deleterious effects. However, recent studies of NOX have created a better understanding of the NOX complex. Comprised of independent cytosolic subunits, p47-phox, p67-phox, p40-phox and Rac, and membrane subunits, gp91-phox and p22-phox, the NOX complex requires a unique activation process through subunit interaction. Of these subunits, p47-phox plays the most important role in activation, binding and translocating the cytosolic subunits to the membrane and anchoring to p22-phox to organize the complex for NOX activation and function. Moreover, these interactions, particularly that between p47-phox and p22-phox, are dependent on phosphorylation initiated by upstream processes involving protein kinase C (PKC). This review will look at these interactions between subunits and with PKC. It will focus on the interaction involving p47-phox with p22-phox, key in bringing the cytosolic subunits to the membrane. Furthermore, the implication of these interactions as a target for NOX inhibitors such as apocynin will be discussed as a potential avenue for further investigation, in order to develop more specific NOX inhibitors based on the inhibition of NOX assembly and activation.

Targeting ferroptosis in rhabdomyosarcoma cells

“…Interestingly, PKCα has recently been described to initiate ferroptotic cell death in dopaminergic neurons in a model of Parkinson's disease . In addition, PKC isoforms have been described as upstream activators of NOX through phosphorylation . There is also evidence of a direct interaction of RAS and PKCζ; and oncogenic RAS has been implied in regulating NOX expression, suggesting an interplay between RAS, PKC and NOX.…”

“…27 In addition, PKC isoforms have been described as upstream activators of NOX through phosphorylation. 32 There is also evidence of a direct interaction of RAS and PKCζ 33 ; and oncogenic RAS has been implied in regulating NOX expression, 34 suggesting an interplay between RAS, PKC and NOX. In the present study, we observed no correlation between RAS mutational status and response to Erastininduced cell death in the investigated RMS cell lines.…”

Advanced oxidation protein products induce pre‐osteoblast apoptosis through a nicotinamide adenine dinucleotide phosphate oxidase‐dependent, mitogen‐activated protein kinases‐mediated intrinsic apoptosis pathway

“…NADPH oxidase is one of the main sources of ROS production, and p47 phox is an important subunit of NADPH oxidase (Rastogi, Geng, Li & Ding, 2016). A previous study showed knockout of p47 phox decreased over 50% of ROS production in p47 phox −/− mice compared with the wild‐type mice, which indicated that decrease in physiological ROS level would cause a negative effect to bone metabolism, and finally resulted in bone loss (Chen et al., 2015).…”

LC3-Associated Phagocytosis and Inflammation

“…The membrane-bound cytochrome b-245 is a heterodimer of two transmembrane proteins: gp91 phox that has electron transferase activity from NADPH to oxygen (O 2 + e − -> O 2 − ) and p22 phox that facilitates the reaction and serves as a docking site for the cytosolic subunits. The regulatory subunits p67 phox , p47 phox and p40 phox aid in complex assembly with the small GTPase Rac1 and are required to fully trigger the ROS generating activity of NOX2 [60, 61]. The p67 phox subunit participates in the catalysis reaction by promoting electron transfer from NADPH and FAD.…”

“…The licensed p40 phox protein is then able to interact with PI3P generated in phagosome membranes [64–66] and brings together the remaining regulatory subunits. After the translocation of the regulatory subunit, the complex is rearranged to achieve full oxidative capacity [60]. NOX2 produces a superoxide anion (O 2 − ) that is rapidly dismutated to hydrogen peroxide in the phagosome lumen (O 2 − + e − + 2H + -> H 2 O 2 ), this and other forms of ROS can cause oxidative damage, particularly relevant to the killing of certain bacteria [67].…”