Trends in Biochemical Sciences
ReviewFeature ReviewThe Nrf2 regulatory network provides an interface between redox and intermediary metabolism
Section snippets
Background
Nrf2 is a cap’n’collar (CNC) basic-region leucine zipper (bZIP) transcription factor that strongly influences intrinsic resistance to oxidative stress and controls adaptive responses to various environmental stressors. Of particular interest is the notion that pharmacological activation of Nrf2 inhibits inflammation and combats degenerative disease. The last review in TiBS about Nrf2 focused on its repression by the E3 ubiquitin ligase substrate adaptor Kelch-like ECH-associated protein (Keap)1
Structural features of Nrf2 protein that dictate its activity
Nrf2 is a modular protein and each of its seven domains, called Nrf2−ECH homology (Neh) domains 1–7, fulfills distinct functions 36, 37, 38. As depicted in Figure 2A, the Neh1 domain comprises the CNC-bZIP region that both dimerizes with small Maf proteins and binds DNA [17]. The Neh2 domain negatively controls Nrf2 because, through its DLG and ETGE motifs 39, 40, 41, it recruits Keap1 (Figure 2B), a dimeric redox-sensitive substrate adaptor for the Cullin (Cul)3–RING (really interesting new
Regulation of Nrf2 activity
It is becoming increasingly clear that the basal activity of Nrf2, as well as the magnitude of its activation in response to stress, is tightly controlled. Thus, under normal homeostatic conditions, Nrf2 is maintained at a low level because it is targeted constitutively for proteasomal degradation by ubiquitylation. Moreover, it is well recognized that electrophiles and oxidants inhibit the proteasomal degradation of Nrf2, thereby enabling the CNC-bZIP protein to accumulate quickly and initiate
DNA repair is augmented by Nrf2
Nrf2-mediated induction of drug-metabolizing enzymes decreases sensitivity to genotoxins 23, 36, 124, 125. The CNC-bZIP factor also influences cellular responses to DNA damage. For example, treatment of human colonic epithelial cells with the Nrf2 activating agent Bardoxolone methyl for 16 h immediately prior to exposure to ionizing radiation (IR) diminished formation of chromosomal aberrations at G1 and S/G2 stages of the cell cycle, and this effect was abolished by knockdown of Nrf2 [126]. It
Role of Nrf2 in intermediary metabolism and mitochondrial function
Nrf2 affects multiple aspects of intermediary metabolism and mitochondrial function. It is either involved directly in the regulation of several key metabolic genes, or it affects their expression indirectly through crosstalk with other transcription factors. Moreover, it may alter indirectly the activity of redox-sensitive metabolic enzymes or redox-sensitive chromatin-remodeling enzymes. Notably, Nrf2 regulates enzymes that catalyze rate-limiting steps or are situated at branching points in
Concluding remarks
Nrf2 plays a pivotal role in cellular adaptation through its ability to induce a diverse battery of genes with cytoprotective actions in response to various stimuli, including redox signaling, inflammation, growth factors, and changes in energy supply. Nrf2 is positively controlled at the transcriptional level by AhR, ARNT, NF-κB, Jun, and Myc, and possibly PPARα, and negatively at the post-translational level by CRLKeap1, SCFβ-TrCP, CRIF1, Siah2, and RNF4. Recent data indicate that repression
Acknowledgments
We are grateful to Prof. Michael L. Ashford (University of Dundee), Dr Douglas A. Bell (NIEHS), Prof. Terje Johansen (University of Tromso), Dr Calum D. Sutherland (University of Dundee) and Prof. Masayuki Yamamoto (Tohoku University) for valuable discussions. The Medical Research Council (MR/J001465/1) and Cancer Research UK (C4909/A13786 and C20953/A10270) fund the work in our laboratories, and we thank them for their support.
References (176)
- et al.
NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer
Trends Biochem. Sci.
(2009) The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity
J. Biol. Chem.
(1991)An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements
Biochem. Biophys. Res. Commun.
(1997)Mitochondrial SKN-1/Nrf mediates a conserved starvation response
Cell Metab.
(2012)Identification of aldo-keto reductases as NRF2-target marker genes in human cells
Toxicol. Lett.
(2013)Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents
Toxicol. Appl. Pharmacol.
(2009)Nitric oxide activates an Nrf2/sulfiredoxin antioxidant pathway in macrophages
Free Radic. Biol. Med.
(2011)Role of sulfiredoxin as a regulator of peroxiredoxin function and regulation of its expression
Free Radic. Biol. Med.
(2012)- et al.
The thioredoxin antioxidant system
Free Radic. Biol. Med.
(2014) Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis
J. Biol. Chem.
(2003)
Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming
Cancer Cell
Nuclear factor erythroid-derived factor 2-related factor 2 regulates transcription of CCAAT/enhancer-binding protein β during adipogenesis
Free Radic. Biol. Med.
Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a “tethering” mechanism: a two-site interaction model for the Nrf2-Keap1 complex
J. Biol. Chem.
Homodimer of two F-box proteins βTrCP1 or βTrCP2 binds to IκBα for signal-dependent ubiquitination
J. Biol. Chem.
Structure of a β-TrCP1-Skp1-β-catenin complex: destruction motif binding and lysine specificity of the SCFβ-TrCP1 ubiquitin ligase
Mol. Cell
Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes
J. Biol. Chem.
Nrf2 protects against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced oxidative injury and steatohepatitis
Toxicol. Appl. Pharmacol.
The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance
Blood
BRCA1 modulates xenobiotic stress-inducible gene expression by interacting with ARNT in human breast cancer cells
J. Biol. Chem.
miR-200a regulates Nrf2 activation by targeting Keap1 mRNA in breast cancer cells
J. Biol. Chem.
Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation
J. Biol. Chem.
The critical role of nitric oxide signaling, via protein S-guanylation and nitrated cyclic GMP, in the antioxidant adaptive response
J. Biol. Chem.
Validation of the multiple sensor mechanism of the Keap1-Nrf2 system
Free Radic. Biol. Med.
Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism
J. Biol. Chem.
Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling
Cancer Cell
USP15 negatively regulates Nrf2 through deubiquitination of Keap1
Mol. Cell
An auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance
J. Biol. Chem.
KEAP1 E3 ligase-mediated downregulation of NF-κB signaling by targeting IKKβ
Mol. Cell
Suppression of NF-κB signaling by KEAP1 regulation of IKKβ activity through autophagic degradation and inhibition of phosphorylation
Cell. Signal.
PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria
Exp. Cell Res.
Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein
J. Biol. Chem.
Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway
J. Biol. Chem.
p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription
J. Biol. Chem.
Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region
Proc. Natl. Acad. Sci. U.S.A.
Stress-activated cap’n’collar transcription factors in aging and human disease
Sci. Signal.
NFE2L3 (NRF3): the Cinderella of the Cap’n’Collar transcription factors
Cell. Mol. Life Sci.
Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway
Proc. Natl. Acad. Sci. U.S.A.
NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development
Proc. Natl. Acad. Sci. U.S.A.
Two adjacent AP-1-like binding sites form the electrophile-responsive element of the murine glutathione S-transferase Ya subunit gene
Proc. Natl. Acad. Sci. U.S.A.
Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity
Proc. Natl. Acad. Sci. U.S.A.
Differential induction of class alpha glutathione S-transferases in mouse liver by the anticarcinogenic antioxidant butylated hydroxyanisole. Purification and characterization of glutathione S-transferase Ya1Ya1
Biochem. J.
Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice
Biochem. J.
Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds
Carcinogenesis
Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis
Nucleic Acids Res.
Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane-treated human breast epithelial cells reveals common expression profiles
Breast Cancer Res. Treat.
Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha
Nucleic Acids Res.
Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks
Nucleic Acids Res.
Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway
Hepatology
Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice
Carcinogenesis
The cystine/glutamate antiporter system xc− in health and disease: from molecular mechanisms to novel therapeutic opportunities
Antioxid. Redox Signal.
Cited by (1526)
The desert woodrat (Neotoma lepida) induces a diversity of biotransformation genes in response to creosote bush resin
2024, Comparative Biochemistry and Physiology Part - C: Toxicology and PharmacologySelenium protects against Pb-induced renal oxidative injury in weaning rats and human renal tubular epithelial cells through activating NRF2
2024, Journal of Trace Elements in Medicine and Biology