Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis

作者：Ping Wang, Jing Geng, Jiahui Gao, Hao Zhao, Junhong Li, Yiran Shi, Bingying Yang, Xiao Chen, Yueyue Linghu, Xiufeng Sun, Xin Chen, Lixin Hong, Funiu Qin, Xun Li, Jau‐Song Yu, Han You, Zengqiang Yuan, Dawang Zhou, Randy L. Johnson, Lanfen Chen · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-08680-6 · 被引用次数：277 · 研究领域：Autophagy in Disease and Therapy、Genomics, phytochemicals, and oxidative stress、Hippo pathway signaling and YAP/TAZ

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.