Novel Protein Interactions Demonstrate Nrf2-Keap1 Functions Beyond Oxidative Response

Abstract

The Nrf2-Keap1 pathway serves as a central regulator that mediates transcriptional responses to xenobiotic and oxidative stimuli. Nrf2 malfunction is highly correlated with many human diseases, but the underlying molecular mechanisms remain to be fully uncovered. Recent studies have shown that Nrf2 and Keap1 can regulate transcripts beyond antioxidant and detoxifying genes. Deng lab research has uncovered that Drosophila Keap1 (dKeap1) and Nrf2 (CncC) proteins can control high-order chromatin structure and development. Here, I expand upon these findings by identifying a molecular interaction of dKeap1 with lamin Dm0 and CncC with Pnr. lamin Dm0 is the Drosophila B-type lamin responsible for the architecture of nuclear lamina and chromatin. Pnr is a conserved Drosophila GATA (GATA4) family transcription factor essential for cardiac and dorsal epidermal development. I also provide preliminary evidence that dKeap1 forms stress induced membraneless organelles. These findings support the model of Nrf2/CncC and Keap1 family proteins as likely candidates for the mediation of epigenetic and developmental adaptation to cellular stress. Fully investigating the mechanisms by which Nrf2/CncC and dKeap1 interact with epigenetic modifiers and regulate developmental processes will help us understand the complicated roles of Nrf2-Keap1 in human disease.