Oxidative Stress Suppresses Nrf2 Protein Synthesis through Global Protein Synthesis Inhibition

Abstract

Oxidative and electrophilic stresses are common aggressors in chronic diseases ranging from arthritis to cancer to neurodegenerative disease. The transcription factor Nrf2 is an essential mediator of the cell’s cytoprotective response to these stressors. Nrf2 is constantly synthesized, ubiquitinated, and degraded with a short half‐life of 20 minutes that maintains low basal Nrf2 protein levels. Electrophiles and oxidative stress cause Nrf2 to accumulate and subsequently to activate cytoprotective genes by modifying cysteines of the Keap1 protein, the repressor that targets Nrf2 for ubiquitination. We previously found that paradoxically, reactive oxygen species (ROS) stimulate the production of cytoprotective proteins, but inhibit Nrf2 protein synthesis, revealing a “Dr. Jekyll and Mr. Hyde” effect of ROS on Nrf2 accumulation. We tested the hypothesis that oxidative conditions that activate the Nrf2 pathway simultaneously inhibit global protein synthesis, thereby suppressing Nrf2 protein synthesis. We investigated both ROS generated by redox cycling of the oxidizable phenol, di‐tert‐butylhydroquinone (dtBHQ), and direct addition of H2O2 to HaCaT keratinocyte cells. We found that 100 μM to 400 μM H2O2 and 50 μM dtBHQ inhibit both Nrf2 protein synthesis and global protein synthesis. Addition of antioxidants, such as the manganese porphyrin MnTMPyP, rescued both Nrf2‐specific and global protein synthesis. Therefore, antioxidants such as MnTMPyP that mitigate the suppressive effects of ROS on global protein synthesis during Nrf2 activation could enhance the Nrf2/cytoprotective response under conditions of electrophilic and oxidative stress.