Abstract
INrf2(Keap1) functions as an adapter for Cul3/Rbx1-mediated degradation of Nrf2. In response to stress, Nrf2 is released from INrf2 and translocates inside the nucleus leading to activation of cytoprotective proteins critical in protection against adverse effects including cancer. We demonstrate here a novel role of heat shock protein 90 (Hsp90) in control of the INrf2 and Nrf2 activation. Hsp90 interacted with INrf2 that leds to stabilization of INrf2 during heat shock stress. Domain mapping showed the requirement of INrf2-NTR and the Hsp90-CLD region for interaction of Hsp90 with INrf2. Heat shock and antioxidants induced Hsp90, and casein kinase 2 (CK2) phosphorylated INrf2Thr55. This led to increased Hsp90-INrf2 interaction, dissociation of the Rbx1/Cul3·INrf2·Nrf2 complex, and activation of Nrf2. Inhibitors of CK2 and Hsp90, and mutation of INrf2Thr55 abolished the Hsp90-INrf2 interaction and downstream signaling. INrf2 is released from Hsp90 once the heat shock or antioxidant stress subsidized, thereby allowing INrf2 to interact with Nrf2 and facilitate Nrf2 ubiquitination and degradation. The results together demonstrate a novel role for the stress-induced Hsp90-INrf2 interaction in regulation of Nrf2 activation and induction of cytoprotective proteins.
Highlights
Cho et al [13] demonstrated that Nrf2 knock-out mice are more sensitive to hyperoxic injury of the lung
It appears that cells contain mechanisms that autoregulate cellular abundance of Nrf2 [19]. These findings suggest that INrf2/Nrf2 signaling plays an important role in cell survival in normal cells, as well as drug resistance in cancer cells [12]
We demonstrate a novel role of heat shock protein 90 (Hsp90) in regulation of INrf2:Nrf2 signaling and induction of chemopreventive proteins
Summary
Cho et al [13] demonstrated that Nrf2 knock-out mice are more sensitive to hyperoxic injury of the lung. The increased Hsp90-INrf2 interaction during heat shock or by antioxidant exposure to cells leads to dissociation of the Rbx1/Cul31⁄7 INrf21⁄7Nrf2 complex and release or activation of Nrf2 and Nrf2 downstream gene expression. Forward and reverse IP and cells showed a Hsp90-V5-dependent increase in INrf2 (Fig. immunoblot analysis showed a significant decrease in threo- 6A, left panel).
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