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, Lanfen Chen*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

185 Scopus citations

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.

Original languageEnglish
Article number755
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 01 12 2019

Bibliographical note

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© 2019, The Author(s).

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