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

Nat Commun. 2019 Feb 14;10(1):755. doi: 10.1038/s41467-019-08680-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cellular Senescence
  • Gene Expression Regulation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RAW 264.7 Cells
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / genetics
  • THP-1 Cells

Substances

  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Reactive Oxygen Species
  • Stk4 protein, mouse
  • Mst2 protein, mouse
  • Protein-Serine-Threonine Kinases