Abstract
Redox imbalance and persistent inflammation are the underlying causes of most chronic diseases. Mammalian cells have evolved elaborate mechanisms for restoring redox homeostasis and resolving acute inflammatory responses. One prominent mechanism is that of inducing the expression of antioxidant, anti-inflammatory and other cytoprotective proteins, while also suppressing the production of pro-inflammatory mediators, through the activation of transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2). At homeostatic conditions, NRF2 is a short-lived protein, which avidly binds to Kelch-like ECH-associated protein 1 (KEAP1). KEAP1 functions as (i) a substrate adaptor for a Cullin 3 (CUL3)-based E3 ubiquitin ligase that targets NRF2 for ubiquitination and proteasomal degradation, and (ii) a cysteine-based sensor for a myriad of physiological and pharmacological NRF2 activators. Here, we review the intricate molecular mechanisms by which KEAP1 senses electrophiles and oxidants. Chemical modification of specific cysteine sensors of KEAP1 results in loss of NRF2-repressor function and alterations in the expression of NRF2-target genes that encode large networks of diverse proteins, which collectively restore redox balance and resolve inflammation, thus ensuring a comprehensive cytoprotection. We focus on the cyclic cyanoenones, the most potent NRF2 activators, some of which are currently in clinical trials for various pathologies characterized by redox imbalance and inflammation.
Highlights
All living organisms are vulnerable to various chemical stressors derived from endogenous and exogenous sources, such as reactive oxygen species (ROS), reactive nitrogen species (RNS) and reactive lipid species (RLS), which play important roles in cell signalling, but when produced in excess lead to oxidative stress
Following Kelch-like ECH-associated protein 1 (KEAP1) inactivation, the newly synthesized or free nuclear factor-erythroid 2 p45-related factor 2 (NRF2) is able to accumulate and translocate into the nucleus where it heterodimerizes with a small musculoaponeurotic fibrosarcoma protein and binds to the antioxidant response elements (ARE) with the consensus sequence 50-TGACxxxGC-30 found in the promoters of its target genes [21]
We measured the distances of the 5 positively charged amino acids mentioned that were adjacent to C151 and found that R135 had the closest proximity to C151 with a distance of 3.6 angstroms (Å), which further supports the findings reported by McMahon and colleagues [64]
Summary
All living organisms are vulnerable to various chemical stressors derived from endogenous and exogenous sources, such as reactive oxygen species (ROS), reactive nitrogen species (RNS) and reactive lipid species (RLS), which play important roles in cell signalling, but when produced in excess lead to oxidative stress. Endogenous stressors, usually produced intracellularly, are derived from metabolic processes such as mitochondrial respiration and inflammation. Exposure to these chemically reactive species promotes cellular macromolecular damage. Following KEAP1 inactivation, the newly synthesized or free NRF2 is able to accumulate and translocate into the nucleus where it heterodimerizes with a small musculoaponeurotic fibrosarcoma (sMAF) protein and binds to the antioxidant response elements (ARE) with the consensus sequence 50-TGACxxxGC-30 found in the promoters of its target genes [21]. The N-terminally lying Neh domain of NRF2 contains two KEAP1 (low- and high-affinity) binding motifs, which are the sequences DLG and ETGE, respectively [26]
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