Reciprocal REGγ-Nrf2 Regulation Promotes Long Period ROS Scavenging in Oxidative Stress-Induced Cell Aging

Increased accumulation of reactive oxygen species (ROS) and decline of adaptive response of antioxidants to oxidative stimuli has been implicated in the aging process. Nuclear factor erythroid 2-related factor 2 (Nrf2) activation is a core event in attenuating oxidative stress-associated aging. The activity is modulated by a more complex regulatory network. In this study, we demonstrate the proteasome activator REGγ function as a new regulator of Nrf2 activity upon oxidative stress in cell aging model induced by hydrogen peroxide (H₂O₂). REGγ deficiency promotes cell senescence in primary MEF cells after H₂O₂ treatment. Accordingly, ROS scavenging is accelerated in WT cells but blunted in REGγ lacking cells during 12-hour recovery from a 1-hour H₂O₂ treatment, indicating long-lasting antioxidant buffering capacity of REGγ. Mechanistically, through GSK-3β inhibition, REGγ enhances the nuclear distribution and transcriptional activity of Nrf2, which is surveyed by induction of phase II enzymes including Ho1 and Nqo1. Meanwhile, Nrf2 mediates the transcriptional activation of REGγ upon H₂O₂ stimulation. More interestingly, short-term exposure to H₂O₂ leads to transiently upregulation and gradually descent of REGγ transcription, however sustained higher REGγ protein level even in the absence of H₂O₂ for 24 hours. Thus, our results establish a positive feedback loop between REGγ and Nrf2 and a new layer of adaptive response after oxidative stimulation that is the REGγ-GSK-3β-Nrf2 pathway.