Reciprocal REG γ -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 γ function as a new regulator of Nrf2 activity upon oxidative stress in cell aging model induced by hydrogen peroxide (H 2 O 2 ). REG γ deficiency promotes cell senescence in primary MEF cells after H 2 O 2 treatment. Accordingly, ROS scavenging is accelerated in WT cells but blunted in REG γ lacking cells during 12-hour recovery from a 1-hour H 2 O 2 treatment, indicating long-lasting antioxidant buffering capacity of REG γ . Mechanistically, through GSK-3 β inhibition, REG γ 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 γ upon H 2 O 2 stimulation. More interestingly, short-term exposure to H 2 O 2 leads to transiently upregulation and gradually descent of REG γ transcription, however sustained higher REG γ protein level even in the absence of H 2 O 2 for 24 hours. Thus, our results establish a positive feedback loop between REG γ and Nrf2 and a new layer of adaptive response after oxidative stimulation that is the REG γ -GSK-3 β -Nrf2 pathway.