Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
Section of Pulmonary and Critical Care Medicine, Atlanta Veterans Affairs Medical Center, Emory University, Decatur, GA 30033, USA.
Free Radic Biol Med. 2017 Dec;113:48-58. doi: 10.1016/j.freeradbiomed.2017.09.011. Epub 2017 Sep 19.
Although critical in phagocytosis in innate immunity, reactive oxygen species (ROS) collaterally inflict damage to host phagocytes because they indiscriminate targets. Since Nrf2 increases the expression of anti-oxidant enzymes that nullifies ROS, ROS activating Nrf2 is a critical negative regulatory step for countering the deleterious effects of ROS. Here, we postulate whether, along with ROS activating Nrf2, NADPH oxidase components also participate in direct activation of Nrf2, contributing to protection from ROS. Our results show that the p47 of the NADPH oxidase, but not p65 or p40, physically binds to Nrf2, activating the Nrf2 function. p47 binding to Nrf2/Keap1 complex suppresses the ubiquitination of Nrf2, while p47 becomes ubiquitinated by Keap1. p47 increases the nuclear translocation of Nrf2 and the expression of Nrf2-dependent genes, whereas genetic ablation of p47 decreases the expression of those genes. In a lipopolysaccharide-induced acute lung inflammation mouse model, selective expression of p47 in mouse lungs induces the expression of Nrf2-dependent genes and is sufficient to suppress neutrophilic lung inflammation. Therefore, our findings suggest that p47 is a novel regulator of Nrf2 function.
尽管活性氧（ROS）在先天免疫的吞噬作用中至关重要，但由于它们无差别地靶向宿主吞噬细胞，因此也会造成损伤。由于 Nrf2 会增加抗氧化酶的表达，从而消除 ROS，因此 ROS 激活 Nrf2 是对抗 ROS 有害影响的关键负调控步骤。在这里，我们假设 NADPH 氧化酶的组成部分是否除了激活 Nrf2 外，还参与了 Nrf2 的直接激活，从而有助于抵御 ROS。我们的结果表明，NADPH 氧化酶的 p47 而不是 p65 或 p40 与 Nrf2 发生物理结合，从而激活了 Nrf2 功能。p47 与 Nrf2/Keap1 复合物结合会抑制 Nrf2 的泛素化，而 p47 则被 Keap1 泛素化。p47 增加了 Nrf2 的核转位和 Nrf2 依赖性基因的表达，而 p47 的基因敲除则降低了这些基因的表达。在脂多糖诱导的急性肺炎症小鼠模型中，p47 在小鼠肺部的选择性表达诱导了 Nrf2 依赖性基因的表达，并足以抑制中性粒细胞性肺炎症。因此，我们的研究结果表明，p47 是 Nrf2 功能的一种新型调节剂。
