Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Nrf2 (NF-E2-Related Factor2)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_540

Synonyms

Historical Background

Nrf2 was found as a member of nuclear factor erythroid 2 (NF-E2) transcription factor family in 1994 (Moi et al. 1994). Nrf2 is a basic Leucine Zipper (bZIP) transcription factor that belongs to the Cap’n’Collar (CNC) family (p45-NFE2, Nrf1, Nrf2, and Nrf3) and is expressed ubiquitously in various tissues (Moi et al. 1994). Yamamoto and his colleagues showed that Nrf2 forms a heterodimer with small Mafs and induces phase-II detoxifying enzymes through antioxidant response elements (AREs) in the promoter regions of the target genes (Tong et al. 2006). A myriad of studies have identified Nrf2 as a sensor that acts against oxidative stress or electrophilic chemicals. In spite of the similarity in nucleotide sequences between Nrf2 and NF-E2, it was not involved in erythropoiesis and development in a murine model.

Oxidative stress is featured by high levels of reactive oxygen species (ROS), which exerts a harmful effect on cellular components and induces defensive responses. ROS originates from hydrogen peroxide (H2O2), superoxide (O2•−), and peroxynitrite (ONOO) form powerful oxidants in the cell. Thus, ROS generation is the fate of aerobic organisms as a natural by-product of oxygen metabolism. In order to avoid cellular damage inflicted by oxidative perturbation, aerobic organisms have developed novel antioxidant defense systems. Among these, Nrf2 and its cytoplasmic repressor kelch-like ECH-associated protein 1 (Keap1) serve sulfhydryl-containing sensors that respond to oxidative stress (Tong et al. 2006); oxidative stress modifies reactive cysteine residues in Keap1 and/or Nrf2. Under no oxidative stimuli, Keap1 binds to the amino-terminal Nrf2-ECH homology 2 (Neh2) domain of Nrf2 and provokes its ubiquitin/proteasomal degradation (Tong et al. 2006). In cells challenged with oxidative stimuli, Keap1 dissociates from Nrf2 and thereby ubiquitin/proteasomal degradation of Nrf2 is hampered. Hence, mice deficient in Nrf2 exacerbate sensitivity to carcinogens or tumorigens, which supports the concept that Nrf2-mediated gene transcription is necessary for the prevention of chemical carcinogenesis by cytoprotective agents (Kensler and Wakabayashi 2010).

An increasing number of studies have described a series of synthetic and phytochemical compounds that activate Nrf2 in cell or animal models (Eggler et al. 2008) (Table 1). Because most of these agents have beneficial effects in a variety of disease models, current pharmacological interventions that target the activity of Nrf2 are expected to advance into novel drug discovery for human diseases.
Nrf2 (NF-E2-Related Factor2), Table 1

Nrf2-activating compounds

Categories

Nrf2 activators

Aromatic organic compounds

BHT (butylated hydroxytoluene)

tBHQ(tert-butylhydroquinone)

BHA (butylated hydroxyanisole)

Dithiolethiones

oltipraz, D3T (1,2-dithiole-3-thione)

Isothiocyantes

sulforaphane

Oleanoic triterpenoids

CDDO-Im (2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide)

Flavonoids

genistein, isoliquiritigenin

Cyclopentenone prostaglandin

15-deoxy-Δ12,14-prostaglandin J2

Polyphenols

EGCG ((−)-epigallocatechin-3-gallate), resveratrol

Regulation of Nrf2 Activity

Domain Structure of Nrf2

Nrf2-ECH homology (Neh) domains are highly conserved in mammalian cells; Nrf2 has six Neh domains (Fig. 1). The domain structure of Nrf2 has been extensively studied by Yamamoto group. Each Neh domains has a distinct role in regulating the activity of Nrf2. First, Neh1 domain contains CNC-bZIP domain that leads to the formation of heterodimer with small Mafs lacking a transactivation domain. Using yeast two hybrid analysis, it has been shown that the Neh2 domain of Nrf2 interacts with Kelch/DGR domain of Keap1, and which induces ubiquitin/proteasomal degradation of Nrf2 via Cul3 ubiquitin ligase (Tong et al. 2006). Whereas Neh2 degron is redox-sensitive, Neh6 degron is not and is required for maximal turnover of Nrf2. Studies have shown that Neh4 and Neh5 domains cooperatively bind with either CREB-binding protein (CBP) or silencing mediator of retinoid and thyroid receptors (SMRT)(Ki et al. 2005) and enhance target gene transactivation (Li and Kong 2009). In addition, the carboxy-terminal Neh3 domain of Nrf2 contributes to Nrf2 transactivation activity.
Nrf2 (NF-E2-Related Factor2), Fig. 1

The domain structures of Nrf2 and Keap1

Degradation of Nrf2 Protein

In normal cells, Nrf2 is short-lived but is rapidly stabilized by oxidative stress. In this process, Keap1 has been recognized as a key repressor molecule that causes ubiquitination/proteasomal degradation. Keap1 is a cysteine-rich protein and serves an oxidative sensor molecule in response to free radical stress. The sulfhydryl modifications of cysteine residues of Keap1 affect Nrf2 degradation (Keap1 has nine reactive cysteine residues that respond to oxidative stress) (Fig. 1). Among them, C273 and C288 are located in the intervening region (IVR) of Keap1, and thus these mutations abrogated the basal inhibitory activity of Nrf2. So, oxidative stress supposedly causes the intermolecular disulfide bond formation of C273 and C288 and, thereby, downregulates Keap1 activity.

Keap1 has two functional domains called Kelch/DGR and broad complex, tramtrack, bric-a-brac (BTB) (Fig. 1) that are involved in Nrf2 degradation. Kelch/DGR domain interacts with Neh2 of Nrf2. BTB domain of Keap1 recruits ubiquitin-ligase complex components and also forms a homodimer of Keap1. Neh2 domain of Nrf2 contains two distinct binding motifs with Kelch/DGR domain of Keap1. One is ETGE motif (formulated as D/N-X-E-T/S-G-E) that has a high affinity (Ka = 20 × 107 M−1) to Kelch/DGR domain of Keap1, whereas the other is DLG motif (formulated as L-X-X-Q-D-X-D-L-G) that has a low affinity (Ka = 0.1 × 107 M−1). X-ray crystallography unraveled that Kelch/DGR domain is a shape of six-bladed β-propeller and each Kelch domain consists of four antiparallel β-strands. Kelch/DGR domain possesses arginine triad (R380, R415 and R483), and these amino acids explain why ETGE motif of Neh2 exerts higher binding affinity than that of DLG. Between these two motifs, 7 lysine residues (7Ks) are located and ubiquitinated by E3 ligase. In addition, the results of nuclear magnetic resonance analysis indicated that the binding ratio of Keap1/Neh2 domain is 2:1 (Li and Kong 2009), suggesting that Keap1 makes homodimer formation.

In addition to Keap1, the ubiquitin-proteasome system is responsible for Nrf2 degradation (Tong et al. 2006). Ubiquitin consists of 76 amino acids and is a highly conserved regulatory protein which designates certain proteins subjected to degradation. E1, an ubiquitin-activating enzyme, generates an ubiquitin-adenylate intermediate using ATP, and then transfers ubiquitin to the active cysteine residue of E1. E2, an ubiquitin-conjugating enzyme, and E3, ubiquitin ligase, cooperatively accomplish the ubiquitination of target proteins. Lysine residue of target protein and C-terminal glycine of ubiquitin forms isopeptide bond by E3 ubiquitin ligase complex. Nrf2 is ubiquitinated by Cul3-BTBkeap1 E3 ligase which belongs to the members of RING domain E3 ligases (Tong et al. 2006). Cul3-BTBkeap1 E3 ligase is composed of Keap1, Rbx1, Cullin3, and Ubc5 (E2 enzyme). As the member of E3 ligase complex, Kelch/DGR domain of Keap1 binds to Nrf2 and the BTB domain recruits the components of E3 ligase complex.

According to these results, Yamamoto’s group proposed “hinge and latch model-two-sites binding mechanism” that describes Keap1-Nrf2 system (Tong et al. 2006). ETGE motif serves “hinge” since it forms a strong binding complex with the Kelch/DGR domain of Keap1 even under oxidative stress. In contrast, DLG motif works as a “latch” which allows Nrf2 to be disoriented under oxidative stress and impedes Nrf2 ubiquitination by Cul3-BTBkeap1 E3 ligase. Reactive cysteines in the IVR domain of Keap1 are modified by oxidative stress. It is postulated that these sulfhydryl modifications may change the conformation of Nrf2 structure (Tong et al. 2006). “Hinge and latch model” successfully accounts for the mode of actions of various Nrf2 activators, including ROS, reactive nitrogen species (RNS), 15-deoxy-Δ12,14-prostaglandin J2, and sulforaphane. Recently, the direct interaction between 154KRR motif in p21 and DLG/ETGE motifs in Nrf2 hampers ubiquitination of Nrf2 by competitively binding with Keap1 (Chen et al. 2009), which supports the model of Yamamoto’s group. Collectively, “hinge and latch model” may account for redox-sensitive Nrf2 activity regulation in association with Keap1.

Nuclear Localization of Nrf2

Nrf2 contains three nuclear localization signal (NLS) motifs and two nuclear export signal (NES) motifs (Li et al. 2006; Li and Kong 2009). NLSN was identified at the amino-terminus, whereas NLSC was at the carboxy-terminus. bNLS is characterized at the basic region of Nrf2. NESTA is localized at the Neh5 transactivation domain, whereas NESzip is at the ZIP domain of Nrf2. Li et al. discovered NESTA motif (175LLSIPELQCLNI186) of Neh5 domain based on the consensus leucine-rich NES motif that is formulated as Φ4(X)2–3Φ3(X)2–3Φ21 (Φ represents hydrophobic amino acids and X represents any amino acids). EGFP-NESTA chimeric protein (a truncated form of Nrf2) promoted cytoplasmic distribution of Nrf2. So, mutation of C183 of NESTA abrogated oxidant-induced ARE activity. The fluorescence resonance energy transfer (FRET) assay failed to show direct interaction between NESTA and Keap1, indicating that nuclear localization of Nrf2 might be modulated by NESTA motif independently of Keap1. Li and Kong have proposed another Nrf2 signaling model in association with Keap1-independent Nrf2 regulation (Li and Kong 2009); in this model, the balance between NLSs and NESs determines the subcellular localization of Nrf2 in response to oxidative stress or antioxidants. NESTA and bNLS motifs possess similar strong driving force for the translocation of Nrf2. Since the driving forces among the motifs are well balanced under normal condition, Nrf2 is expelled to cytoplasm. Nrf2 is translocated into the nucleus when redox-sensitive NESTA is halted by oxidative stress (i.e., NESzip is redox-insensitive).

The Signals of Nrf2 Regulation

Phosphatidylinositol 3-Kinase

Phosphatidylinositol 3-kinase (PI3K) phosphorylates phosphatidylinositol-4,5-trisphosphate [PtdIns(4,5)P2] into phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3], which is the secondary messenger for other kinases such as serine-threonine Akt kinase.  PI3K regulates microfilaments and translocation of actin-associated proteins (Fig. 2). In response to oxidative stress, PI3K activation induces actin cytoskeleton rearrangement. Actin depolymerization promotes translocation of a complex of Nrf2 and actin into the nucleus and enables activating Nrf2 to bind to the ARE for phase II enzyme induction by oxidative stress (Kang et al. 2005).
Nrf2 (NF-E2-Related Factor2), Fig. 2

The signaling pathways for Nrf2 activity regulation

Protein Kinase C Delta

Protein kinase C (PKC) disseminates signals into target molecules in response to extracellular stimuli. PKC pathway may be an initial triggering step for recognizing cellular redox state transition. Pickett’s group revealed that Nrf2 activation requires phosphorylation at S40 by PKCδ critical for nuclear translocation of Nrf2 (Fig. 2) (Kaspar et al. 2009). Recently, both phosphorylation of Nrf2 S40 by PKCδ and antioxidant-induced modification of Keap1 C151 contribute to stabilization and nuclear translocation of Nrf2 (Niture et al. 2009).

Glycogen Synthase Kinase-3β

It has been shown that tyrosine kinase Fyn phosphorylated Y568 of Nrf2 and regulates chromosomal region maintenance 1 (Crm1/exportin 1)-mediated nuclear export of Nrf2 (Fig. 2). Glycogen synthase kinase-3β (GSK-3β) was identified as an upstream kinase of Fyn (Kaspar et al. 2009). Inhibition of GSK-3β induces nuclear accumulation of Nrf2 and transcriptionally activates the induction of Nrf2 target genes (i.e., phase-II enzymes). Hydrogen peroxide directly phosphorylates Y216 of GSK-3β, which leads to GSK-3β activation, implying that ROS affects GSK-3β-mediated Nrf2 activity regulation (Kaspar et al. 2009).

Nrf2 Target Genes and Biological Functions

The Genes That Contain ARE(s)

The induction of phase-II detoxification enzymes and phase-III efflux transporters through ARE depends on the activity of Nrf2. Major antioxidant enzymes contain one or more functional ARE(s) in their promoter regions (Table 2). Once Nrf2 dissociates from its Keap1 binding in response to oxidative stress, the activating Nrf2 translocates into the nucleus and binds ARE comprised in the promoters of target genes. Unlike canonical bZIP proteins, Nrf2 has no ability to form homodimer (Li and Kong 2009). Instead, Nrf2 forms heterodimer with small Maf proteins such as MafF/G/K which lack canonical transactivation domain. In addition, Nrf2 is directly acetylated by p300/CREB-binding protein (CBP) under the condition of arsenite-induced stress (Sun et al. 2009). Eighteen lysine residues were identified as acetylation sites in Neh1 DNA-binding domain. Intriguingly, combined lysine-to-arginine mutations on the acetylation sites unaffected the stability of Nrf2, but compromised its DNA-binding activity (Sun et al. 2009). Nrf2 activation and target gene transcription contribute to the detoxification and excretion of detrimental xenobiotics. Phytochemicals and synthetic compounds may have cytoprotective and chemopreventive effects through Nrf2 activation (Eggler et al. 2008). Hence, a deficiency of Nrf2 abrogates the abilities of these agents to protect cells against toxic chemicals or physical stresses, as shown in the experiments using animals or cells.
Nrf2 (NF-E2-Related Factor2), Table 2

Nrf2 target genes

Functions

Target genes

Phase-I enzymes

None

Phase-II enzymes

GSTA2

NQO1

heme oxygenase-1

UDP-glucuronosyltransferases (UGT) 1A6

glutamate-cysteine ligase modifier (GCLM)

glutamate-cysteine ligase catalytic subunits (GCLC)

Phase-III enzymes

Multidrug resistance protein (MRP) 2/3/4/5/6, Organic anion transporting polypeptide (Oatp) 1a1/2b1

Iron-binding protein

Ferritin H

As the cores of energy metabolism, mitochondria regulate the balance between constitutive and excessive levels of cellular ROS. The mitochondrial respiratory chain not only produces ROS under a basal condition, but also serves a major ROS source under pathological situations. Oxidative stress causes mitochondrial permeability transition, mitochondrial dysfunction, and apoptosis. Hence, the maintenance of mitochondrial function is crucial in protecting cells or organs from toxicants. Compared to nuclear DNA, mitochondria DNA are vulnerable to oxidative stress because of two reasons: (1) mitochondria are the organelles that produce ROS via electron transport chain, and (2) mitochondria DNA repair mechanisms are insufficient. Therefore, the induction of phase-II detoxifying enzymes by Nrf2 might be closely associated with cytoprotective effect against toxicant-induced injury, which may result from not only a decrease in cellular ROS, but protection of mitochondria (Kensler et al. 2007). Collectively, it is hypothesized that the roles of Nrf2 in apoptosis include regulation of redox-homeostasis, increase in adaptive antioxidant capacity, activation of phase-II detoxifying enzymes, and mitochondrial protection, all of which contribute to cell viability.

Cancer

Exposure to toxic external stimuli such as xenobiotics and viral infections might cause genetic defects and thus increase cancer incidence. Carcinogenesis is induced by complex mechanisms which are characterized as multiple genetic defects and uncontrolled growth. These genetically defected genes often have effects on signal transduction pathways regarding cell survival, proliferation, and trans-differentiation. In particular, excess ROS provokes DNA damage such as point mutation, deletion-insertion, and microsatellite instability. Thus, it is a reasonable prediction that antioxidants and antioxidative enzymes contribute to preventing genetic defects of cells from radical stress. Various experimental models have shown that induction of antioxidative and cytoprotective enzymes by chemicals contributes to cancer chemoprevention, and which accompanies Nrf2 activation in most cases.

Many research groups have made a huge effort to develop Nrf2 activators as chemopreventive agents. However, it is now accepted that constitutive Nrf2 activation may also contribute to malignancy and radiation/drug resistance in cancer. The mutations in Keap1 and overwhelming expression of Nrf2 occur in the tissue of lung cancer patients (Lau et al. 2008). Mutated Keap1 possesses substantially impeded binding affinity with Nrf2, leading to augmented anti-apoptotic and antioxidative effects. Therefore, some cancer cells with Keap1 mutations acquire the capacity to survive from harsh tumor microenvironment through Nrf2 activation. Recently, Kensler and Wakabayashi proposed “U-Shaped model” that describes the modulation of cancer risk in terms of the Keap1-Nrf2 pathway (Kensler and Wakabayashi 2010). Nrf2 activation is clinically practical only between the biologically effective dose (BED) and a maximal-tolerated dose (MTD). Low level of Nrf2 expression makes cells susceptible to carcinogenesis or toxicity, whereas high level of Nrf2 expression in tumor might attribute to cancer malignancy.

Lately, epigenetic regulatory pathway of Nrf2-Keap1 has been underscored in cancer cells by several research groups. Hypermethylation of CpG islands of Keap1 was discovered in lung adenocarcinoma. In addition, CpG island methylations in the promoter region of Nrf2 gene was identified in transgenic adenocarcinoma of mouse prostate, but not in normal tissue (Yu et al. 2010). Thus, Nrf2 level and its downstream target gene expression are substantially repressed in this prostate tumor model. These results suggest that the epigenetic approach is also necessary for the understanding of Nrf2 role in cancer.

Cardiovascular Diseases

ROS is involved in the pathologic processes of cardiovascular diseases such as atherosclerosis, hypertension, and coronary heart disease. In cardiovascular diseases, ROS production (H2O2 and O2) is increased due to NAD(P)H oxidase, peroxidase, and cyclooxygenase. In particular, vascular smooth muscle cells (VSMCs) and endothelial cells are the major sources of ROS. Nrf2 is a potential target for the intervention of cardiovascular diseases. Studies have shown that the Nrf2/heme oxygenase-1 (HO-1) pathway is associated with the inhibition of VSMC proliferation and migration, and which helps provide a condition for obtaining anti-atherosclerotic activity (Li et al. 2009). After balloon angioplasty in rabbit aorta, local adenoviral transfer of Nrf2 contributes to reducing VSMC proliferation, oxidative stress, and inflammatory responses (Li et al. 2009). However, the lack of change in neointimal hyperplasia by ectopic Nrf2 expression implies that Nrf2 may induce anti-apoptosis of VSMCs. In human aortic endothelial cells, laminar flow, but not oscillatory flow, induces Nrf2 activation and its target gene transactivation (Li et al. 2009); the degree of Nrf2 activation differs between atherosclerosis-resistant and atherosclerosis-susceptible regions of the mouse aorta. Although Nrf2 regulates antioxidant defense system, it still remains elusive what the exact molecular mechanism of Nrf2 is in cardiovascular system.

Summary

Oxidative stress is critical in homeostasis and survival of aerobic organisms. Nrf2 target gene induction plays a role in antioxidant defense systems. In cells challenged with oxidative stimuli, Keap1 is not able to degrade Nrf2 so that antioxidative and cytoprotective enzymes are activated. So, Nrf2-mediated gene induction by pharmacological agents may account for cancer chemoprevention, and amelioration of hepatic and cardiovascular diseases. However, incremental Nrf2 activation was observed in cancer tissues, implying that it may also contribute to invoking cancer malignancy and chemoresistance. The exact role and mechanism of Nrf2 regulation and its functional consequences are still elusive, and further molecular and clinical investigation is requisite.

Notes

Acknowledgments

This work was supported by the National Research Foundation of Korea grant funded by the Korea government (MEST) (No. 2009-0063233) and the World Class University project (which is also funded by Korea government) (R32-2008-000-10098-0).

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Sang Geon Kim
    • 1
  • Woo Hyung Lee
    • 1
  • Young Woo Kim
    • 1
  1. 1.College of PharmacySeoul National UniversitySeoulKorea