NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease.
NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease.
复制标题
亚基相互作用的 NOX 激活和疾病的潜在机制。
DOI：
10.3389/fncel.2016.00301
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发表时间：
2016
影响因子：
5.3
通讯作者：
Ding Y
中科院分区：
文献类型：
--
作者：
Rastogi R;Geng X;Li F;Ding Y
烟酰胺腺嘌呤二核苷酸磷酸（NAPDH）氧化酶（NOX）是一种以NADPH为底物产生超氧阴离子和活性氧的酶复合物。对于免疫系统以及细胞信号传导至关重要，NOX也参与各种疾病状态的病理学。特别是，它是许多神经系统疾病，包括中风，TBI和神经退行性疾病中不可或缺的参与者。在病理学上，NOX产生过量的ROS，超过身体的抗氧化能力来中和它们，导致氧化应激和异常信号。这种普遍性使其成为有吸引力的治疗靶标，因此，已经研究和开发了NOX抑制剂以对抗NOX的有害作用。然而，最近对NOX的研究使人们对NOX复合物有了更好的了解。NOX复合物由独立的胞质亚基p47-phox、p67-phox、p40-phox和Rac以及膜亚基gp 91-phox和p22-phox组成，需要通过亚基相互作用的独特活化过程。在这些亚基中，p47-phox在活化、结合和易位胞质亚基至膜以及锚定至p22-phox以组织复合物用于NOX活化和功能中起最重要的作用。此外，这些相互作用，特别是p47-phox和p22-phox之间的相互作用，依赖于由涉及蛋白激酶C（PKC）的上游过程启动的磷酸化。这篇综述将着眼于这些亚基之间的相互作用，并与PKC。它将集中在涉及p47-phox与p22-phox的相互作用，这是将胞质亚基带到膜上的关键。此外，这些相互作用的影响作为一个目标，如夹竹桃素的NOX抑制剂将被讨论作为一个潜在的途径进行进一步研究，以开发更具体的NOX抑制剂的基础上抑制NOX组装和激活。
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.