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

Ping Wang, Jing Geng, Jiahui Gao, Hao Zhao, Junhong Li, Yiran Shi, Bingying Yang, Chen Xiao, Yueyue Linghu, Xiufeng Sun, Xin Chen, Lixin Hong, Funiu Qin, Xun Li, Jau-Song Yu, Han You, Zengqiang Yuan, Dawang Zhou, Randy L. Johnson and Lanfen Chen ()
Additional contact information
Ping Wang: Xiamen University
Jing Geng: Xiamen University
Jiahui Gao: Xiamen University
Hao Zhao: Xiamen University
Junhong Li: Xiamen University
Yiran Shi: Xiamen University
Bingying Yang: Xiamen University
Chen Xiao: Xiamen University
Yueyue Linghu: Xiamen University
Xiufeng Sun: Xiamen University
Xin Chen: Xiamen University
Lixin Hong: Xiamen University
Funiu Qin: Xiamen University
Xun Li: Medical College of Xiamen University
Jau-Song Yu: Chang Gung University and Liver Research Center, Chang Gung Memorial Hospital at Linkou
Han You: Xiamen University
Zengqiang Yuan: The Brain Science Center, Beijing Institute of Basic Medical Sciences
Dawang Zhou: Xiamen University
Randy L. Johnson: University of Texas, M.D. Anderson Cancer Center
Lanfen Chen: Xiamen University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-08680-6

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