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

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.
Mesh Terms:
Animals, Cells, Cultured, Cellular Senescence, Gene Expression Regulation, HEK293 Cells, HeLa Cells, Humans, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, NF-E2-Related Factor 2, Oxidative Stress, Protein-Serine-Threonine Kinases, RAW 264.7 Cells, Reactive Oxygen Species, Signal Transduction, THP-1 Cells
Nat Commun
Date: Dec. 14, 2018
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