Regulation of Nrf2—an update

Abstract

Nrf2:INrf2 (Keap1) are cellular sensors of oxidative and electrophilic stress. Nrf2 is a nuclear factor that controls the expression and coordinated induction of a battery of genes which encode detoxifying enzymes, drug transporters (MRPs), anti-apoptotic proteins and proteasomes. In the basal state, Nrf2 is constantly degraded in the cytoplasm by its inhibitor, INrf2. INrf2 functions as an adapter for Cul3/Rbx1 E3 ubiquitin ligase mediated degradation of Nrf2. Chemicals including antioxidants, tocopherols including α-tocopherol (vitamin E), phytochemicals and radiations antagonize the Nrf2:INrf2 interaction and leads to the stabilization and activation of Nrf2. The signaling events involve pre-induction, induction and post-induction responses that tightly control Nrf2 activation and repression back to the basal state. Oxidative/electrophilic signals activate unknown tyrosine kinase(s) in a pre-induction response which phosphorylates specific residues on Nrf2 negative-regulators, INrf2, Fyn and Bach1, leading to their nuclear export, ubiquitination and degradation. This prepares nuclei for unhindered import of Nrf2. Oxidative/electrophilic modification of INrf2cysteine151 followed by PKC phosphorylation of Nrf2serine40 in the induction response results in the escape or release of Nrf2 from INrf2. Nrf2 is thus stabilized and translocates to the nucleus resulting in a coordinated activation of gene expression. This is followed by a post-induction response that controls the ‘switching off’ of Nrf2-activated gene expression. GSK3β under the control of AKT and PI3K, phosphorylates Fyn leading to Fyn nuclear localization. Fyn phosphorylates Nrf2Y568 resulting in nuclear export and degradation of Nrf2. The activation and repression of Nrf2 provides protection against oxidative/electrophilic stress and associated diseases, including cancer. However, deregulation of INrf2 and Nrf2 due to mutations may lead to nuclear accumulation of Nrf2 that reduces apoptosis and promotes oncogenesis and drug resistance.

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

“…Consistent with the notion that accumulation of Nrf2 is indicative of cells under stress adjusting to neutralize oxidative damage (Niture et al, 2014; Zhang et al, 2004), we found a marked increase in Nrf2 protein levels in DS HF and Dp16 MEF cellular homogenates (Figure 3a,c) (probed with SC722 antibody, see Methods, Supporting Information Figures S5A–C and S7B,C) and strong immunofluorescent signal for pNrf2ser40 (pNrf2) in the nuclei of DS cells (see Methods, Figure 3b; Supporting Information Figures S6A and S7D,E), consistent with the presence of chronic oxidative stress. Transcriptional upregulation of Nrf2‐dependent antioxidant response elements (ARE) was confirmed by qPCR (Supporting Information Figure S8).…”

“…Nrf2 stabilization in DS cells depends on its phosphorylation by PKCδ, which in turn is activated by casp3, as shown by specific inhibitor assays (Niture et al, 2014), demonstrating the increasingly complex role of caspases in physiological and cytoprotective signaling pathways beyond their well‐characterized role in apoptosis (Unsain & Barker, 2015). Alternative and sometimes complementary antioxidant pathways mediated by p53 and FOXO have been described in the context of more stringent oxidative conditions (Gorrini et al, 2013).…”

Nuclear Factor Erythroid 2-Related Factor 2 Down-Regulation in Oral Neutrophils Is Associated with Periodontal Oxidative Damage and Severe Chronic Periodontitis

“…The Nrf2 pathway controls the expression of a wide array of genes essential for production of cytoprotective factors, its activation leading to cell survival and tissue protection during oxidative stress conditions. 11,12 It has also been shown that osteoclastic bone resorption is substantially promoted in Nrf2-deficient osteoclast precursor cells compared with WT cells. 28 This must be kept in mind when interpreting our results because the lack of AO also affects the osteoclasts in addition to the PMNs.…”

“…9,10 Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates gene transcription of a large group of antioxidant and phase 2 detoxifying enzymes playing a central role in cellular defense against oxidative and electrophilic insults. 11,12 In response to oxidative stress, cytoplasmic Nrf2 is released from Kelchlike ECH-associated protein 1 and binds to antioxidant response elements in the promoter region of many antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), NAD(P)H:quinone oxidoreductase, glutathione S-transferase, heme oxygenase-1, glutathione peroxidase, glutamate cysteine ligase, and peroxiredoxin I. 12 In addition, because NF-kBemediated production of cytokines and chemokines, such as tumor necrosis factor-a, IL-6, IL-8 (CXCL8), and chemokine ligand 2, is likely to be reductionoxidation regulated, Nrf2 may play critical roles in control of inflammatory injury.…”

“…11,12 In response to oxidative stress, cytoplasmic Nrf2 is released from Kelchlike ECH-associated protein 1 and binds to antioxidant response elements in the promoter region of many antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), NAD(P)H:quinone oxidoreductase, glutathione S-transferase, heme oxygenase-1, glutathione peroxidase, glutamate cysteine ligase, and peroxiredoxin I. 12 In addition, because NF-kBemediated production of cytokines and chemokines, such as tumor necrosis factor-a, IL-6, IL-8 (CXCL8), and chemokine ligand 2, is likely to be reductionoxidation regulated, Nrf2 may play critical roles in control of inflammatory injury. Nrf2 was shown to play important roles in rheumatoid arthritis, gastrointestinal, renal, brain, skin, and pulmonary inflammation, and atherosclerosis.…”