Pi J., Leung L., Xue P., Wang W., Hou Y., Liu D., Yehuda-Shnaidman E., Lee C., Lau J., Kurtz T.W., et al. Rockwell C.E., Zhang M., Fields P.E., Klaassen C.D. Increased Nrf2 activation in livers from Keap1-knockdown mice increases expression of cytoprotective genes that detoxify electrophiles more than those that detoxify reactive oxygen species. Cold Spring Harb Symp Quant Biol 50:643650, PubMed Nuclear Factor Erythroid 2-related Factor 2 Deficiency Exacerbates Lupus Nephritis in B6/lpr mice by Regulating Th17 Cell Function. Gorrini C., Baniasadi P.S., Harris I.S., Silvester J., Inoue S., Snow B., Joshi P.A., Wakeham A., Molyneux S.D., Martin B., et al. Under ER stress conditions, HRD1 is induced and binds to the Neh 4-5 domains of NRF2 that mediate NRF2 ubiquitylation and degradation in cirrhotic livers [21]. Intracellular iron storage protein ferritin, including ferritin heavy chain (FTH) and ferritin light chain (FTL), sequesters excess free iron in a protein cage that limits irons redox switching. Pujato, M., Kieken, F., Skiles, A.A., Tapinos, N. and Fiser, A. NRF2 induces expression of glucose transporter GLUT1 that allows increased glucose import into glycolytic flux [77]. (2009) High-resolution DNA-binding specificity analysis of yeast transcription factors. However, Nfe2l2-null mice on C57BL6;129SV mix background in mice showed decreased adipose tissue mass, formation of small adipocytes, and protected against weight gain and obesity induced by HFD [91]. Merry T.L., Ristow M. Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) mediates exercise-induced mitochondrial biogenesis and the anti-oxidant response in mice. NRF2 is a hub that compiles emergency signals derived from misfolded protein accumulation to facilitate a coordinated transcriptional response. Nucleic Acids Res, 42, 13500-13512. The enzyme RNA polymerase catalyzes the chemical reactions that synthesize RNA, using the gene's DNA as a template. (2013) Early evolution of the T-box transcription factor family. Alignment of the Predicted Amino Acid Sequences of Proteins Related to GPAT4. Yarosz E.L., Chang C.H. NRF2, a Transcription Factor for Stress Response and Beyond. In addition, stress-induced PERK phosphorylates NRF2, resulting in dissociation of NRF2/KEAP1 complexes and NRF2 activation [27]. Quantitative real-time PCR assays were performed in triplicate on an ABI Prism 7000 sequence detection system (Applied Biosystems) using ACTIN2 expression as an endogenous control, except when WIN1 expression was measured in silenced and overexpressing lines. (, Zimmermann, P., Hirsch-Hoffmann, M., Hennig, L., and Gruissem, W. (, Oxford University Press is a department of the University of Oxford. ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression. Hu Q., Ren J., Li G., Wu J., Wu X., Wang G., Gu G., Ren H., Hong Z., Li J. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (, NRF2, metabolism, UPR, oxidative stress, inflammation, autophagy, proteostasis, transcription factor, The architecture of Nuclear factor erythroid 2-related factor 2 (NRF2), Kelch-like-ECH-associated protein 1 (KEAP1), and -transducin repeat-containing protein (TrCP). The bZip in the Neh1 domain heterodimerizes with small musculoaponeurotic fibrosarcoma proteins (sMAF) K, G, and F as well as other bZip proteins to recognize antioxidant response elements (ARE) for activation of gene transcription, whereas the Neh2 domain contains ETGE and DLG motifs that specifically interact with Kelch domain of Kelch-like-ECH-associated protein 1 (KEAP1) to mediate NRF2 ubiquitination and degradation (Figure 1B) [2]. The diluted chromatin was precleared using 40 L of ChIP bufferequilibrated sheared salmon sperm DNA/Protein G agarose beads (Update) for 2 h at 4C. As a control, plants were sprayed with a mock solution containing 0.015% (v/v) Silwet and 0.033% (v/v) ethanol. A decrease in PK activity would favor buildup of glycolytic intermediates and their channeling into the synthesis of amino acids, nucleic acids, and phospholipids. BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. Iizuka T., Ishii Y., Itoh K., Kiwamoto T., Kimura T., Matsuno Y., Morishima Y., Hegab A.E., Homma S., Nomura A., et al. High oxidative phosphorylation increases mitochondrial electron leak and thus increases ROS levels. Transcription factors are proteins that bind to DNA-regulatory sequences (enhancers and silencers), usually localized in the 5 -upstream region of target genes, to modulate the rate of gene transcription. Interaction of TFIIA with TBP also results in the exclusion of negative (repressive) factors that might otherwise bind to TBP and interfere with PIC formation. Wu T., Zhao F., Gao B., Tan C., Yagishita N., Nakajima T., Wong P.K., Chapman E., Fang D., Zhang D.D. This is a preview of subscription content, access via your institution. http://creativecommons.org/licenses/by/4.0/, Nuclear factor erythroid 2-Related Factor 2. Huang H.C., Nguyen T., Pickett C.B. The Role of Reactive Oxygen Species in Regulating T Cell-mediated Immunity and Disease. Briefly, 150 to 300 mg of leaf tissue, 40 mg of flower tissue, or 3 mg of petals (200 petals) were extensively delipidated, the resulting residues dried, transmethylated, and then silylated in 50 to 100 L BSTFA:TMCS (99:1). (2009) Diversity and complexity in DNA recognition by transcription factors. PKM2 is highly expressed in cancer cells that coordinates high energy requirements with high anabolic activities to support cancer cell proliferation [81]. Phase II enzymes traditionally refer to the enzymes catalyzing the conjugation reactions, such as glutathione S-transferase (GST), UDP-glucuronosyltransferase (UGT), UDP-glucuronic acid synthesis enzymes, and HO-1 [70,71]. The TF2DNA database provides comprehensive information about transcription factor binding motifs and their regulated genes for five model . NRF2 also regulates its own NFE2L2 mRNA transcription. The mitochondria provide the cell with energy from oxidative phosphorylation, which is intimately linked to the production of ROS. The impact of post-transcriptional regulation of NFE2L2 on the pathogenesis of disease remains to be evaluated. The DNA fragments were cleaned up using a Qiaquick PCR DNA purification kit (Qiagen). Harbison, C.T., Gordon, D.B., Lee, T.I., Rinaldi, N.J., Macisaac, K.D., Danford, T.W., Hannett, N.M., Tagne, J.B., Reynolds, D.B., Yoo, J. et al. KEAP1 is a redox-regulated adaptor for the CUL3- RBX1 ubiquitin ligase complex and it binds NRF2 through its C-terminal Kelch domain, which interacts with the DLG and ETGE motifs in the Neh2 domain of NRF2, resulting in ubiquitination of NRF2 in the cytoplasm and degradation by the 26 S proteasome [3]. We apologize to the authors whose work could not be cited due to space constraints. Prez-Rueda, E. and Collado-Vides, J. The transcription factor BTB and CNC homology 1 (BACH1), which is essential in controlling heme level through the inhibition of heme oxygenase-1 (HO)-1 gene, competes with NRF2-sMAF interaction at ARE sites for transcriptional repression of NRF2 target NAD(P)H:quinone oxidoreductase1 (NQO1) [52]. NFE2L2 gene contains ARE within its promoter region that renders NRF2 the ability to directly activate its own transcription, providing a positive feedback mechanism to amplify NRF2 effects [29]. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Dendogram Obtained by Hierarchical Cluster Analysis of 42 Arabidopsis Lines Based on FTIR Spectra Sampled from Dark-Grown Hypocotyls. Two micrograms of total RNA were treated with DNase I (Ambion) prior to reverse transcription by SuperScript II reverse transcriptase (Invitrogen) in a 20-L reaction volume. Recent studies have identified new NRF2 target genes and revealed several new functions of NRF2 that go beyond its redox-regulating capacities, including regulation of inflammation, autophagy, metabolism, proteostasis, and unfolded protein response (UPR), particularly in the context of carcinogenesis. Ludtmann M.H., Angelova P.R., Zhang Y., Abramov A.Y., Dinkova-Kostova A.T. Nrf2 affects the efficiency of mitochondrial fatty acid oxidation. Transcription Factors. NRF2 stimulates the mitochondrial biogenesis program through activation of nuclear respiratory factor-1 (NRF-1), which transcribes the key mitochondrial biogenesis factors transcription factor A, mitochondrial (TFAM) and transcription factor B2, mitochondrial (TFBM2) [115]. Biochem J 311:705716, Kim MJ, Kim JK, Shin JS, Suh MC (2007) The SebHLH transcription factor mediates trans-activation of the SeFAD2 gene promoter throught binding to E- and G-box elements. NRF2 and the Hallmarks of Cancer. In the NRF2 activated context, autophagy-targeted therapy could be ineffective. Inflammation is triggered when innate immune cells detect infection or tissue injury. Emerging evidence shows that NRF2 lies at the center of a complex regulatory network and establishes NRF2 as a truly pleiotropic transcription factor. Th2 skewing by activation of Nrf2 in CD4(+) T cells. Activity of NRF2 is modulated at multiple levels, including transcriptional regulation (NF-B, AhR-ARNT, ATF4, and other transcription factors, cofactors), post-transcriptional regulation (miRNA, RBPs, alternative splicing), post-translational regulation (ERK, JNK, PKC, CK2, PERK, GSK3, p38), and regulation of NRF2 stability (KEAP1, TrCP, HRD1, WDR23, CRIF1). In addition, NRF2 directly controls expression of transcriptional co-activator peroxisome proliferator activated receptor gamma co-activator 1 alpha (PGC-1a), a master regulator of mitochondrial function and biogenesis [118]. Correspondence to Phase III enzymes transport the conjugated metabolites after Phase II and are mainly drug efflux transporters, such as multidrug resistance-associated proteins (MDR), breast cancer resistant protein (BCRP), ATP-binding cassette g5 (ABCG5) and g8 (ABCG8) [71]. Supplemental Table 2. NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly. Sha L.K., Sha W., Kuchler L., Daiber A., Giegerich A.K., Weigert A., Knape T., Snodgrass R., Schroder K., Brandes R.P., et al. Glutamine transporter solute carrier family 1 member 5 (SLC1A5) mediates glutamine uptake and it is transcriptionally activated by NRF2 [87]. Scharer, C.D., McCabe, C.D., Ali-Seyed, M., Berger, M.F., Bulyk, M.L. Notch-Nrf2 axis: Regulation of Nrf2 gene expression and cytoprotection by notch signaling. RNA was treated with DNase I (Ambion), and the quality of the samples was checked using the RNA 6000 Nano LabChip kit (Agilent). Science, 324, 1720-1723. Biliverdin is further metabolized to bilirubin, which subsequently serves as an antioxidant free radical scavenger and can be glucuronidated for excretion, by either biliverdin reductase A (BLVRA) or biliverdin reductase B (BLVRB). Sixty microliters were removed for an input sample and the rest split into 600-L aliquots. Cell, 158, 1431-1443. NRF2 can directly activate G6PD, PGD, TKT, and TALDO1 by binding to the well-conserved AREs in their promoters, thereby directing carbon flux towards the PPP [35]. Hou J., Zhang H., Sun B., Karin M. The immunobiology of hepatocellular carcinoma in humans and mice: Basic concepts and therapeutic implications. (, Xu, X.J., Dietrich, C.R., Delledonne, M., Xia, Y.J., Wen, T.J., Robertson, D.S., Nikolau, B.J., and Schnable, P.S. Nrf2 induces interleukin-6 (IL-6) expression via an antioxidant response element within the IL-6 promoter. Damaged, misfolded, oxidized, or short-lived proteins are degraded by 26S proteasome, which consists of a 20S core and a 19S regulatory subunit. Future studies need to address how the NRF2-dependent network changes from a physiological (beneficial) to a pathological (adversary) condition that can provide insights into mechanisms of disease pathogenesis. NRF2-induced expression of ARE-containing cytoprotective genes in response to cell stress forms a network of cooperating enzymes involved in phase I, II, and III drug detoxification reaction and elimination of pro-oxidants to maintain cellular homeostasis [70].