Abstract
Transcription factor Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses the induction of pro-inflammatory cytokine genes. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase. Keap1 regulates the activity of Nrf2 and acts as a sensor for oxidative and electrophilic stresses. In this review, we discuss the molecular mechanisms by which the Keap1-Nrf2 system senses and regulates the cellular response to environmental stresses. In particular, we focus on the multiple stress-sensing mechanisms of Keap1 and novel regulatory functions of Nrf2.
Highlights
Our body is equipped with a defense system that up-regulates the expression levels of cytoprotective enzyme genes
Upon exposure to oxidative or electrophilic stresses, Keap1 loses its ability to ubiquitinate Nrf2, allowing Nrf2 to accumulate in the nucleus and activate its target genes
Recent studies expanded our knowledge on the targets of the Keap1–Nrf2 system, and the molecular mechanisms underpinning how this system senses a variety of environmental stresses
Summary
Transcription factor Nrf (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Upon exposure to oxidative or electrophilic stresses, Keap loses its ability to ubiquitinate Nrf, allowing Nrf to accumulate in the nucleus and activate its target genes. In response to oxidative/electrophilic stimuli (or inducers), the Keap1–Cul complex loses ubiquitin ligase activity (or the floodgate function), and Nrf accumulates in the nucleus and activates target genes (Fig. 2B). In Keap1C151S mouse embryonic fibroblasts (MEFs) and peritoneal macrophages, the Cys-151 residue was found to be indispensable for the accumulation of Nrf in response to a set of electrophilic chemicals These Nrf inducers include DEM, tert-butylhydroquinone, dimethyl fumarate, nitric oxide (NO), TFM-735, and CDDO-Im [44, 45, 53] and are categorized into Class I as Cys-151-preferring inducers (Fig. 3). Because NEKO mice likely have other phenotypes that have not yet been studied, further analysis of NEKO mice will provide new insights for a better understanding of the physiological functions of Nrf
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