Review
Feature Review
The Nrf2 regulatory network provides an interface between redox and intermediary metabolism

https://doi.org/10.1016/j.tibs.2014.02.002Get rights and content

Highlights

  • Nrf2 is part of a complex regulatory network that responds to environmental cues.

  • Nrf2 allows adaptation by inducing cytoprotective genes and maintaining redox homeostasis.

  • Nrf2 transcription is positively regulated by AhR, ARNT, NF-κB, Jun, and Myc.

  • Nrf2 protein stability is controlled by CRLKeap1, SCFβ-TrCP, CRIF1, Siah2, and RNF4.

  • Nrf2 influences metabolism, including lipid, carbohydrate, amino acid, and nucleotide.

Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, also called Nfe2l2) is a transcription factor that regulates the cellular redox status. Nrf2 is controlled through a complex transcriptional/epigenetic and post-translational network that ensures its activity increases during redox perturbation, inflammation, growth factor stimulation and nutrient/energy fluxes, thereby enabling the factor to orchestrate adaptive responses to diverse forms of stress. Besides mediating stress-stimulated induction of antioxidant and detoxification genes, Nrf2 contributes to adaptation by upregulating the repair and degradation of damaged macromolecules, and by modulating intermediary metabolism. In the latter case, Nrf2 inhibits lipogenesis, supports β-oxidation of fatty acids, facilitates flux through the pentose phosphate pathway, and increases NADPH regeneration and purine biosynthesis; these observations suggest Nrf2 directs metabolic reprogramming during stress.

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.

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