Abstract
Molecular responses mediated by sensor proteins are important for biological defense against electrophilic stresses, such as xenobiotic electrophile exposure. NF-E2-related factor 2 (Nrf2) has an essential function as a master regulator of such cytoprotective molecular responses along with sensor protein Kelch-like ECH-associated protein 1. This review focuses on Nrf2 activation and its involvement with the protective defense systems under electrophilic stresses integrated with our recent findings that reactive sulfur species (RSS) mediate detoxification of electrophiles. The Nrf2 pathway does not function redundantly with the RSS-generating cystathionine γ-lyase pathway, and vice versa.
Highlights
Humans are exposed to various xenobiotic electrophiles on a daily basis through their dietary habits, living environment, lifestyle and so on
Numerous studies confirmed that NF-E2-related factor 2 (Nrf2) acts as a master regulator for cytoprotective molecules along with its activation mechanism through Kelch-like ECH-associated protein 1 (Keap1) as a sensor protein
Reactive sulfur species (RSS)-mediated protection against electrophiles appears to be a primary defense system compared with the Nrf2-dependent detoxification system with GSH because RSS are constitutively produced by cystathionine γ-lyase (CSE), whereas the gene expression of glutamate cysteine ligase (GCL), GSH S-transferase (GST) and multidrug resistance-associated protein (MRP) associated with conjugation with GSH and subsequent excretion of GSH adducts into the extracellular space are cooperatively regulated by Nrf2 [21,23]
Summary
Humans are exposed to various xenobiotic electrophiles on a daily basis through their dietary habits, living environment, lifestyle and so on. The chemical modification of sensor proteins with reactive thiols by xenobiotic electrophiles at low doses results in the activation of cellular signal transduction pathways to maintain cellular homeostasis [5,6,8,10,11,12]. This adaptive cellular response to electrophiles is termed electrophilic signaling and involves both basal metabolism and oxidative/inflammatory responses [13,14,15,16]. Our recent study clarified the contributions of Nrf and CSE to the blockage of electrophilic stresses in a parallel mode [20]
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