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 REG gamma function as a new regulator of Nrf2 activity upon oxidative stress in cell aging model induced by hydrogen peroxide (H2O2). REG gamma deficiency promotes cell senescence in primary MEF cells after H2O2 treatment. Accordingly, ROS scavenging is accelerated in WT cells but blunted in REG gamma lacking cells during 12-hour recovery from a 1-hour H2O2 treatment, indicating long-lasting antioxidant buffering capacity of REG gamma. Mechanistically, through GSK-3 beta inhibition, REG gamma 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 gamma upon H2O2 stimulation. More interestingly, short-term exposure to H2O2 leads to transiently upregulation and gradually descent of REG gamma transcription, however sustained higher REG gamma protein level even in the absence of H2O2 for 24 hours. Thus, our results establish a positive feedback loop between REG gamma and Nrf2 and a new layer of adaptive response after oxidative stimulation that is the REG gamma-GSK-3 beta-Nrf2 pathway.