Alternative titles; symbols
HGNC Approved Gene Symbol: NFE2L2
Cytogenetic location: 2q31.2 Genomic coordinates (GRCh38) : 2:177,230,303-177,264,727 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.2 | Immunodeficiency, developmental delay, and hypohomocysteinemia | 617744 | Autosomal dominant | 3 |
The NFE2L2 gene encodes a transcription factor that binds to the antioxidant response element (ARE), thereby activating the expression of genes involved in the response to different cellular insults, such as oxidative stress (summary by Huppke et al., 2017).
NFE2 (601490), NFE2L1 (163260), and NFE2L2 comprise a family of human genes encoding basic leucine zipper (bZIP) transcription factors. They share highly conserved regions that are distinct from other bZIP families, such as JUN (165160) and FOS (164810), although remaining regions have diverged considerably from each other (Chan et al., 1995).
Using the AP1 (see JUN; 165160)- and NFE2-binding sequences from the control region of the beta-globin locus (HBB; 141900) to screen a human myelogenous leukemia cell line cDNA library, followed by screening a fetal liver cDNA library, Moi et al. (1994) cloned full-length NFE2L2, which they called NRF2. The deduced 589-amino acid protein has a calculated molecular mass of 66.1 kD. NRF2 has a hydrophilic N-terminal domain, followed by an acidic region with characteristics of a DNA activation domain, a central cnc homology region conserved among NFE2 family members, a basic DNA-binding domain, and a C-terminal leucine zipper dimerization domain that contains charged residues predicted to impede homodimer formation. Northern blot analysis detected a 2.4-kb NRF2 transcript in all adult and fetal tissues and cell lines examined except fetal blood, bone marrow, and bone. Highest expression was detected in adult muscle, kidney, and lung and in fetal liver and muscle. In vitro transcription and translation resulted in a protein with an apparent molecular mass of 96 kD.
Using a reporter gene assay, Moi et al. (1994) demonstrated that the putative N-terminal acidic transactivation domain of NRF2 was functional.
Superinduction of the SSAT gene (SAT1; 313020) is associated with the antineoplastic activity of several antitumor polyamine analogs. Wang et al. (1999) found that PMF1 (609176) mRNA was also induced in a lung tumor cell line sensitive to polyamine analogs, but it was not induced in an insensitive lung tumor cell line. Cotransfection of PMF1 and NRF2 activated transcription from the polyamine-responsive element of the SSAT promoter in a reporter assay, and PMF1 was the rate-limiting component. Wang et al. (1999) concluded that PMF1 mediates SSAT transcriptional induction by acting in cooperation with NRF2.
Wang et al. (2001) demonstrated that the NRF2-PMF1 interaction requires the leucine zipper region of NRF2 and the C-terminal coiled-coil region of PMF1. Mutations that interrupted either of these regions altered the ability of the proteins to interact, and they lost their ability to regulate transcription of the SSAT gene.
Using a yeast 2-hybrid assay, He et al. (2001) found that mouse Nrf2 interacted with rat Atf4 (604064). Coimmunoprecipitation and mammalian 2-hybrid analyses confirmed the interaction. An Nrf2-Atf4 dimer bound a stress response element sequence from an Nrf2 target gene, Ho1 (HMOX1; 141250). Additional experiments suggested that ATF4 regulates HO1 expression in a cell-specific manner, possibly in a complex with NRF2.
Using small-interfering RNA (siRNA) to disrupt DJ1 expression in a human nonsmall cell lung carcinoma cell line, Clements et al. (2006) showed that DJ1 (602533) was required for the expression of several genes, including the NRF2-regulated antioxidant enzyme NQO1 (125860). Without DJ1, NRF2 protein was unstable, and transcriptional responses were decreased both basally and after induction. DJ1 was indispensable for NRF2 stabilization by affecting NRF2 association with KEAP1 (606016), an inhibitor protein that promotes ubiquitination and degradation of NRF2.
Oxidized phospholipids, such as oxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphocholine), have proinflammatory and proatherogenic effects, and they also have beneficial effects in vascular cells via induction of antioxidant enzymes. Jyrkkanen et al. (2008) showed that oxPAPC increased nuclear accumulation of NRF2 in human umbilical vein endothelial cells (HUVECs) and increased the expression of the antioxidants HMOX1 (141250), GCLM (601176), and NQO1 (125860), all of which contain antioxidant response elements (AREs) in their 5-prime flanking sequences. Knockdown of NRF2 via small interfering RNA reversed the induction of GCLM and NQO1 by oxPAPC, but it had less effect on HMOX1 induction. Reporter gene assays and chromatin immunoprecipitation analysis demonstrated that oxPAPC activated ARE and increased the binding of NRF2 to NQO1 and HMOX1 AREs. Furthermore, induction of Hmox1, Gclm, and Nqo1 by oxPAPC was reduced in Nrf2-null mouse carotid arteries compared with wildtype. Jyrkkanen et al. (2008) concluded that activation of NRF2 by oxidized phospholipids limits their deleterious effects in the vasculature.
The identification of somatic mutations that disrupt the NRF2-KEAP1 interaction to stabilize NRF2 and increase the constitutive transcription of NRF2 target genes indicated that enhanced reactive oxygen species (ROS) detoxification and additional NRF2 functions may in fact be tumorigenic. DeNicola et al. (2011) investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras (190070), Braf (164757), and Myc (190080), and found that ROS are actively suppressed by these oncogenes. Kras(G12D) (190070.0005), Braf(V619E) and Myc(ERT2) each increased transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a mechanism for the activation of the Nrf2 antioxidant program evident in primary cells and tissues of mice expressing KRas(G12D) and BRaf(V619E), and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impaired KRas(G12D)-induced proliferation and tumorigenesis in vivo. Thus, DeNicola et al. (2011) concluded that the NRF2 antioxidant and cellular detoxification program represents a theretofore unappreciated mediator of oncogenesis.
Eades et al. (2011) found that microRNA-200A (MIR200A; 612090) bound to the 3-prime UTR of the KEAP1 transcript, leading to degradation of the mRNA. Epigenetic silencing of MIR200A in breast cancer cells resulted in KEAP1 dysregulation, inhibition of NRF2 transcriptional activity, and reduced expression of NQO1. Overexpression of MIR200A in human breast cancer cells or treatment of a mouse model of breast cancer with a histone deacetylase inhibitor enhanced MIR200A-dependent KEAP1 downregulation and restored NRF2 expression.
Using integrated metabolic tracing and transcription profiling of a large panel of non-small cell lung cancer (NSCLC) cell lines to characterize the activity and regulation of the serine/glycine biosynthetic pathway in NSCLC, DeNicola et al. (2015) showed that the activity is highly heterogeneous and is regulated by NRF2, a transcription factor frequently deregulated in NSCLC. DeNicola et al. (2015) found that NRF2 controls the expression of the key serine/glycine biosynthesis enzyme genes PHGDH (606879), PSAT1 (610936), and SHMT2 (138450) via ATF4 to support glutathione and nucleotide production. DeNicola et al. (2015) showed that expression of these genes confers poor prognosis in human NSCLC.
Bambouskova et al. (2018) showed that itaconate and dimethylitaconate induce electrophilic stress, react with glutathione and subsequently induce both NRF2-dependent and -independent responses. Bambouskova et al. (2018) found that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to Toll-like receptor stimulation via inhibition of I-kappa-B-zeta (608004) protein induction. The regulation of I-kappa-B-zeta is independent of NRF2, and the authors identified ATF3 (603148) as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of dimethylitaconate could ameliorate IL17 (603149)-I-kappa-B-zeta-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway.
Mills et al. (2018) showed that itaconate, an endogenous metabolite, is required for the activation of the antiinflammatory transcription factor NRF2 by lipopolysaccharide in mouse and human macrophages. Mills et al. (2018) found that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273, and 297 on the protein KEAP1 (606016), enabling NRF2 to increase the expression of downstream genes with antioxidant and antiinflammatory capacities. The activation of NRF2 is required for the antiinflammatory action of itaconate. Mills et al. (2018) described the use of a cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. The authors showed that type I interferons boost the expression of IRG1 (615275) and itaconate production. Itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Mills et al. (2018) concluded that itaconate is a crucial antiinflammatory metabolite that acts via NRF2 to limit inflammation and modulate type I interferons.
Bollong et al. (2018) identified a small-molecule inhibitor of the glycolytic enzyme PGK1 (311800), and revealed a direct link between glycolysis and NRF2 signaling. Inhibition of PGK1 resulted in accumulation of the reactive metabolite methylglyoxal, which selectively modified KEAP1 (606016) to form a methylimidazole crosslink between proximal cysteine and arginine residues. This posttranslational modification resulted in the dimerization of KEAP1, the accumulation of NRF2, and activation of the NRF2 transcriptional program. Bollong et al. (2018) concluded that their results demonstrated the existence of direct interpathway communication between glycolysis and the KEAP1-NRF2 transcriptional axis, and provided insight into the metabolic regulation of the cellular stress response.
Moi et al. (1994) determined that the NFE2L2 gene contains 5 exons and spans over 11 kb. The first intron is over 6 kb long.
By fluorescence in situ hybridization, Chan et al. (1995) demonstrated that the NFE2L2 gene, which they symbolized NRF2, is located on 2q31. Although the genes encoding NFE2, NFE2L1, and NFE2L2 are located on chromosomes 12, 17, and 2, respectively, they were probably derived from a single ancestor by chromosomal duplication. Other genes mapped to the same regions of the 3 chromosomes are related to one another, e.g., are members of the collagen, integrin, and HOX gene families.
In 4 unrelated patients with immunodeficiency, developmental delay, and hypohomocysteinemia (IMDDHH; 617744), Huppke et al. (2017) identified 4 different de novo heterozygous missense mutations in the NFE2L2 gene (600492.0001-600492.0004). All mutations affected 1 of 2 motifs (ETGE or DLG) in the N-terminal Neh2 domain that facilitates the binding of inhibitory KEAP1 (606016) molecules. Fibroblasts derived from 1 patient showed increased levels of mutant NFE2L2 and increased expression of multiple genes, including those involved in the stress response. The strongest increase in expression was seen for AKR1C1 (600449) and AKR1B10 (604707). Patient erythrocytes showed increased activity of G6PD (305900) and GSR (138300), indicating downstream activation of NFE2L2 target genes in vivo. Patient cells also showed an imbalance in cytosolic redox balance, with a more reducing, i.e., more negative, resting state redox balance compared to controls. Treatment of patient cells with the antioxidant luteolin reduced the NFE2L2 levels by up to 90%, while treatment with ascorbic acid was less consistently effective. Overall, the findings suggested that the mutations increased NFE2L2 levels in the absence of stress and caused constitutive chronic activation of stress response genes, consistent with a gain-of-function effect.
Chan et al. (2001) found that Nrf2 knockout mice are highly susceptible to acetaminophen (APAP). With doses of APAP that were tolerated by wildtype mice, the Nrf2 -/- mice died of liver failure. When hepatic glutathione was depleted after a dose of 400 mg/kg of APAP, the wildtype mice were able to compensate and regain the normal glutathione level. In contrast, the glutathione level in the knockout mice was not compensated and remained low. The results highlighted the importance of Nrf2 in the regulation of glutathione synthesis and cellular detoxification processes.
Lee et al. (2004) reported that mice with targeted disruption of Nrf2 showed regenerative immune-mediated hemolytic anemia. A chronic increase in oxidative stress due to decreased antioxidant capacity sensitized erythrocytes and caused hemolytic anemia in Nrf2 -/- mice, suggesting a pivotal role of the Nrf2-antioxidant responsive element pathway in the cellular antioxidant defense system.
Rangasamy et al. (2004) reported that Nrf2 -/- mice had earlier-onset and more extensive cigarette smoke-induced emphysema than wildtype littermates. Emphysema in NRF2-deficient mice exposed to cigarette smoke for 6 months was associated with more pronounced bronchoalveolar inflammation, enhanced alveolar expression of a marker of oxidative stress, and an increased number of apoptotic alveolar septal cells. Microarray analysis identified expression of nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lung that may work in concert to counteract cigarette smoke-induced oxidative stress and inflammation. Rangasamy et al. (2004) concluded that the responsiveness of the NRF2 pathway may act as a major determinant of susceptibility to cigarette smoke-induced emphysema by upregulating antioxidant defenses and decreasing lung inflammation and alveolar cell apoptosis.
Wildtype rodents have brownish-yellow incisors, the color representing iron content. Iron is deposited into the mature enamel by ameloblasts that outline enamel surface of the teeth. Yanagawa et al. (2004) found that genetically engineered Nrf2-deficient mice had grayish-white incisors. Micro x-ray imaging analysis revealed that the iron content of the Nrf2-deficient mouse incisors was significantly decreased compared to that of wildtype mice. Iron was aberrantly deposited in the papillary layer cells of the enamel organ in Nrf2-deficient mice, suggesting that the iron transport from blood vessels to ameloblasts was disturbed. Yanagawa et al. (2004) also found that ameloblasts of Nrf2 null mice showed degenerative atrophy at the late maturation stage, which gave rise to the loss of iron deposition to the surface of mature enamel. They concluded that the enamel organ of Nrf2-deficient mice has a reduced iron transport capacity, which results in both the enamel cell degeneration and disturbance of iron deposition onto the enamel surface.
Thimmulappa et al. (2006) observed that lipopolysaccharide (LPS) treatment, as well as cecal ligation and puncture (CLP), induced greater mortality and pulmonary inflammation, including Tnf (191160) secretion and Nfkb (see 164011) activity, in Nrf2 -/- mice compared with wildtype mice. Microarray and RT-PCR analyses showed that Nrf2 controlled the early surge of a number of proinflammatory cytokines and chemokines and their regulators, as well as antioxidative genes (e.g., GCLC; 606857). Immunoblot analysis showed greater degradation of Ikba (NFKBIA; 164008) and increased Ikk (see 600664) activity in Nrf2 -/- mice after treatment with either LPS or TNF. Luciferase reporter assays showed that N-acetyl-cysteine antioxidant pretreatment significantly attenuated Nfkb-mediated activity in Nrf2 -/- cells and abrogated LPS-induced proinflammatory gene expression in Nrf2 -/- mice. Thimmulappa et al. (2006) concluded that NRF2 regulates the innate immune response during sepsis and improves survival by maintaining redox homeostasis and restraining proinflammatory signaling.
Caloric restriction is the most potent intervention known to both protect against carcinogenesis and extend life span in laboratory animals. Using Nrf2 -/- mice, Pearson et al. (2008) showed that Nrf2 was responsible for most of the anticarcinogenic effects of caloric restriction, but it was dispensable for increased insulin sensitivity and life span extension.
In a 9-year-old boy (patient 1) with immunodeficiency, developmental delay, and hypohomocysteinemia (IMDDHH; 617744), Huppke et al. (2017) identified a de novo heterozygous c.239C-A transversion (c.239C-A, NM_006164.4) in exon 2 of the NFE2L2 gene, resulting in a thr80-to-lys (T80K) substitution at a conserved residue in the ETGE motif of the Neh2 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database.
In a 13-year-old boy (patient 2) with immunodeficiency, developmental delay, and hypohomocysteinemia (IMDDHH; 617744), Huppke et al. (2017) identified a de novo heterozygous c.241G-A transition (c.241G-A, NM_006164.4) in exon 2 of the NFE2L2 gene, resulting in a gly81-to-ser (G81S) substitution at a conserved residue in the ETGE motif of the Neh2 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database.
In a 14-year-old boy (patient 3) with immunodeficiency, developmental delay, and hypohomocysteinemia (IMDDHH; 617744), Huppke et al. (2017) identified a de novo heterozygous c.91G-A transition (c.91G-A, NM_006164.4) in exon 2 of the NEF2L2 gene, resulting in a gly31-to-arg (G31R) substitution at a conserved residue in the DLG motif of the Neh2 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database.
In a 1.5-year-old girl (patient 4) with immunodeficiency, developmental delay, and hypohomocysteinemia (IMDDHH; 617744), Huppke et al. (2017) identified a de novo heterozygous c.235G-A transition (c.235G-A, NM_006164.4) in exon 2 of the NFE2L2 gene, resulting in a glu79-to-lys (E79K) substitution at a conserved residue in the ETGE motif of the Neh2 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. The patient had an unaffected twin sister who did not carry the mutation.
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