Transcriptional Regulation by Nrf2

Abstract

Significance: Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that coordinates the basal and stress-inducible activation of a vast array of cytoprotective genes. Understanding the regulation of Nrf2 activity and downstream pathways has major implications for human health. Recent Advances: Nrf2 regulates the transcription of components of the glutathione and thioredoxin antioxidant systems, as well as enzymes involved in phase I and phase II detoxification of exogenous and endogenous products, NADPH regeneration, and heme metabolism. It therefore represents a crucial regulator of the cellular defense mechanisms against xenobiotic and oxidative stress. In addition to antioxidant responses, Nrf2 is involved in other cellular processes, such as autophagy, intermediary metabolism, stem cell quiescence, and unfolded protein response. Given the wide range of processes that Nrf2 controls, its activity is tightly regulated at multiple levels. Here, we review the different modes of regulation of Nrf2 activity and the current knowledge of Nrf2-mediated transcriptional control.

Critical issues: It is now clear that Nrf2 lies at the center of a complex regulatory network. A full comprehension of the Nrf2 program will require an integrated consideration of all the different factors determining Nrf2 activity.

Future directions: Additional computational and experimental studies are needed to obtain a more dynamic global view of Nrf2-mediated gene regulation. In particular, studies comparing how the Nrf2-dependent network changes from a physiological to a pathological condition can provide insight into mechanisms of disease and instruct new treatment strategies.

Keywords: Nrf2; antioxidant response; transcription.

FIG. 1.

Structure of the human Nrf2 protein. The Nrf2 protein comprises seven Neh domains. The Neh1 CNC-bZIP domain is responsible for DNA binding and dimerization with the small Maf proteins; the Neh2 domain mediates the interaction with Keap1 through the DLG and ETGE motifs and contains seven lysine residues that are targets of ubiquitylation; the Neh3, Neh4 and Neh5 domains are transactivation domains; the Neh6 domain is a serine-rich region that regulates Nrf2 stability; and the Neh7 domain is involved in RXRα binding. bZIP, basic-region leucine zipper; CNC, cap “n” collar; Keap1, Kelch-like ECH-associated protein 1; Neh, Nrf2-ECH homology; Nrf2, nuclear factor E2-related factor 2; RXRα, retinoid X receptor α.

FIG. 2.

The classical view of Nrf2 activation and response. Under unstressed conditions, Nrf2 is bound to Keap1, constantly ubiquitylated by the Cul3 E3 ubiquitin ligase and subsequently degraded by the proteasome. In response to stress, Keap1 is inactivated, resulting in Nrf2 stabilization. Nrf2 translocates to the nucleus where it heterodimerizes with the small Maf proteins, binds to the ARE and activates the transcription of its target genes. ARE, antioxidant response element.

FIG. 3.

The Nrf2-regulated cytoprotective defense system. Through the coordinated regulation of GSH and TXN production, utilization and regeneration, NADPH regeneration, heme and iron metabolism, ROS and xenobiotic detoxification, Nrf2 provides the main cytoprotective defense system in the cell. GSH, glutathione; HMOX1, heme oxygenase 1; Idh1, isocitrate dehydrogenase 1; NAPDH, nicotinamide adenine dinucleotide phosphate; Nqo1, NADPH quinone dehydrogenase 1; Pgd, 6-phosphogluconate dehydrogenase; ROS, reactive oxygen species; TXN, thioredoxin.

FIG. 4.

Mechanisms of regulation of Nrf2 activity. The mechanisms of modulation of Nrf2 activity include the regulation of transcription, mRNA processing, translation, subcellular localization, protein stability, and availability of binding partners. Arrows indicate activating regulation, and bars indicate inhibitory regulation. β-TrCP, β-transducing repeat-containing protein; AhR, aryl hydrocarbon receptor; BRCA1, breast cancer susceptibility 1; NF-κB, nuclear factor-κB; PI3K, phopshoinositide 3-kinase; PKC, protein kinase C.

FIG. 5.

Nrf2-mediated induction of gene expression. (a) Nrf2 selects the genes to be activated by binding as a heterodimer with sMaf to the ARE in promoter regions of the target genes. The recognition of the ARE can be influenced by the cooperation or competition with other activators or repressors. (b) Nrf2 recruits co-activators, components of the transcription machinery and nucleosome-remodeling complexes through protein–protein interactions to make the chromatin structure accessible to the Pol II machinery. (c) Together, co-activators and chromatin remodelers favor the recruitment of Pol II and the general transcription factors to form the PIC. Following phosphorylation of Ser2 and Ser5 in Pol II CTD transcription starts. CTD, carboxy-terminal domain; PIC, pre-initiation complex; Pol II, RNA polymerase II; sMaf, small masculoaponeurotic fibrosarcoma.

FIG. 6.

Dissecting the Nrf2 network. Nrf2 lies at the center of a complex regulatory network. Nrf2-mediated regulation of gene expression depends on the cellular context, the inducing agent, the levels of Nrf2 activation, the recognition of the ARE, binding partners, cofactors and competitors, the crosstalk with other signaling pathways, and the epigenetic landscape of the target gene promoter, among others.