Reciprocal REG-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 REG function as a new regulator of Nrf2 activity upon oxidative stress in cell aging model induced by hydrogen peroxide (HO). REG deficiency promotes cell senescence in primary MEF cells after HO treatment. Accordingly, ROS scavenging is accelerated in WT cells but blunted in REG lacking cells during 12-hour recovery from a 1-hour HO treatment, indicating long-lasting antioxidant buffering capacity of REG. Mechanistically, through GSK-3 inhibition, REG 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 REG upon HO stimulation. More interestingly, short-term exposure to HO leads to transiently upregulation and gradually descent of REG transcription, however sustained higher REG protein level even in the absence of HO for 24 hours. Thus, our results establish a positive feedback loop between REG and Nrf2 and a new layer of adaptive response after oxidative stimulation that is the REG-GSK-3-Nrf2 pathway.