Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis
Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis
复制标题
巨噬细胞通过Mst-Nrf2轴实现针对氧化应激诱导衰老的自我保护
DOI：
10.1038/s41467-019-08680-6
复制
发表时间：
2019-02-14
影响因子：
16.6
通讯作者：
Chen, Lanfen
中科院分区：
文献类型：
--
作者：
Wang, Ping;Geng, Jing;Chen, Lanfen
吞噬细胞产生活性氧是机体抵抗病原体的主要防御机制。然而，细胞的自我保护机制，对这种潜在的损害，从氧化应激仍然不清楚。在这里，我们表明，激酶Mst 1和Mst 2（Mst 1/2）的感觉ROS和维持细胞的氧化还原平衡，通过调节抗氧化剂转录因子Nrf 2的稳定性。位点特异性ROS释放将Mst 1/2从胞质溶胶募集到吞噬体或线粒体膜，随后ROS激活Mst 1/2以磷酸化kelch样ECH相关蛋白1（Keap 1）并阻止Keap 1聚合，从而阻断Nrf 2泛素化和降解以保护细胞免受氧化损伤。用抗氧化剂N-乙酰半胱氨酸处理破坏ROS诱导的Mst 1/2与吞噬体或线粒体的相互作用，从而减少Mst-Nrf 2信号。因此，Mst 1/2的缺失导致氧化损伤增加、吞噬细胞老化和死亡。因此，我们的研究结果确定Mst-Nrf 2轴作为一个重要的ROS传感和抗氧化机制，在抗菌反应。
Reactive oxygen species (ROS) production in phagocytes is a major defense mechanism against pathogens. However, the cellular self-protective mechanism against such potential damage from oxidative stress remains unclear. Here we show that the kinases Mst1 and Mst2 (Mst1/2) sense ROS and maintain cellular redox balance by modulating the stability of antioxidant transcription factor Nrf2. Site-specific ROS release recruits Mst1/2 from the cytosol to the phagosomal or mitochondrial membrane, with ROS subsequently activating Mst1/2 to phosphorylate kelch like ECH associated protein 1 (Keap1) and prevent Keap1 polymerization, thereby blocking Nrf2 ubiquitination and degradation to protect cells against oxidative damage. Treatment with the antioxidant N-acetylcysteine disrupts ROS-induced interaction of Mst1/2 with phagosomes or mitochondria, and thereby diminishes the Mst-Nrf2 signal. Consistently, loss of Mst1/2 results in increased oxidative injury, phagocyte ageing and death. Thus, our results identify the Mst-Nrf2 axis as an important ROS-sensing and antioxidant mechanism during an antimicrobial response.