Nrf2-dependent Induction of Proteasome and Pa28αβ Regulator Are Required for Adaptation to Oxidative Stress

Background: Adaptation to oxidative stress involves increased expression of 20 S proteasome, Pa28, and immunoproteasome. Results: Blocking Nrf2 prevents proteasome and Pa28 induction, and Nrf2 is required for full adaptation. Conclusion: Adaptation occurs through Nrf2-dependent induction of 20 S proteasome and Pa28, whereas immunoproteasome is induced independently. Significance: The Nrf2 signal transduction pathway controls 20 S proteasome/Pa28 contributions to stress-adaptation, but not immunoproteasome contributions. The ability to adapt to acute oxidative stress (e.g. H 2 O 2 , peroxynitrite, menadione, and paraquat) through transient alterations in gene expression is an important component of cellular defense mechanisms. We show that such adaptation includes Nrf2-dependent increases in cellular capacity to degrade oxidized proteins that are attributable to increased expression of the 20 S proteasome and the Pa28 (11 S) proteasome regulator. Increased cellular levels of Nrf2, translocation of Nrf2 from the cytoplasm to the nucleus, and increased binding of Nrf2 to antioxidant response elements (AREs) or electrophile response elements (EpREs) in the 5-untranslated region of the proteasome 5 subunit gene (demonstrated by chromatin immunoprecipitation (or ChIP) assay) are shown to be necessary requirements for increased proteasome/Pa28 levels, and for maximal increases in proteolytic capacity and stress resistance; Nrf2 siRNA and the Nrf2 inhibitor retinoic acid both block these adaptive changes and the Nrf2 inducers DL-sulforaphane, lipoic acid, and curcumin all replicate them without oxidant exposure. The immunoproteasome is also induced during oxidative stress adaptation, contributing to overall capacity to degrade oxidized proteins and stress resistance. Two of the three immunoproteasome subunit genes, however, contain no ARE/EpRE elements, and Nrf2 inducers, inhibitors, and siRNA all have minimal effects on immunoproteasome expression during adaptation to oxidative stress. Thus, immunoproteasome appears to be (at most) minimally regulated by the Nrf2 signal transduction pathway.