State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
Cancer Research Center of Xiamen University, Xiamen, Fujian, 361102, China.
Nat Commun. 2019 Feb 14;10(1):755. doi: 10.1038/s41467-019-08680-6.
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.
吞噬细胞中活性氧（ROS）的产生是抵御病原体的主要防御机制。然而，细胞自身针对这种潜在氧化应激损伤的保护机制尚不清楚。在这里，我们发现激酶 Mst1 和 Mst2（Mst1/2）可以感知 ROS，并通过调节抗氧化转录因子 Nrf2 的稳定性来维持细胞内的氧化还原平衡。ROS 特异性释放将 Mst1/2 从细胞质招募到吞噬体或线粒体膜，随后 ROS 激活 Mst1/2 磷酸化 Kelch 样 ECH 相关蛋白 1（Keap1），阻止 Keap1 聚合，从而阻止 Nrf2 的泛素化和降解，保护细胞免受氧化损伤。抗氧化剂 N-乙酰半胱氨酸的处理会破坏 ROS 诱导的 Mst1/2 与吞噬体或线粒体的相互作用，从而减弱 Mst-Nrf2 信号。一致地，Mst1/2 的缺失会导致氧化损伤增加、吞噬细胞衰老和死亡。因此，我们的结果表明 Mst-Nrf2 轴是抗菌反应中一种重要的 ROS 感应和抗氧化机制。
