Binding partners of NRF2: Functions and regulatory mechanisms

https://doi.org/10.1016/j.abb.2019.108184Get rights and content

Abstract

NRF2 is a redox-sensitive transcription factor that plays an important role in protecting organisms against diverse types of electrophiles or oxidants. The level of NRF2 is maintained low in normal cells, but highly elevated in cancer provoking chemoresistance or radioresistance. It is now recognized that NRF2 does not merely maintain the redox balance, but also plays significant roles in autophagy, apoptosis, cell cycle progression, and stem cell differentiation, all of which could be possibly attributable to the existence of multiple binding proteins. In the present manuscript, we summarize direct binding partners of NRF2 and illustrate how they bind to NRF2 and regulate its stability or activity.

Section snippets

NRF2 is a transcription factor for phase II cytoprotective enzymes

Oxidative phosphorylation is a well-defined cellular process that produces adenosine triphosphate (ATP) by transferring electrons from reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH 2) to the mitochondrial ATP synthase [1]. Oxidative phosphorylation is the major source of ATP in aerobic organisms. Because oxygen functions as a final electron acceptor during oxidative phosphorylation, the formation of intracellular reactive oxygen species (ROS) inevitably

KEAP1 binds to the Neh2 domain of NRF2

Using a yeast-two hybrid assay with the Neh2 domain as bait, Yamamoto and colleagues discovered that KEAP1 binds to the Neh2 domain of NRF2 [19]. After the discovery that KEAP1 acts as an adaptor for Cullin 3 (CUL3)-based E3 ubiquitin ligase [20], the exact function of KEAP1 was characterized: NRF2 is tightly regulated by KEAP1-mediated ubiquitination [21]. NRF2 is maintained at low levels under basal conditions due to constant proteolysis in the cytoplasm. However, oxidants or electrophiles

Coactivators and corepressors serve as binding proteins on the Neh5/6 domain of NRF2

CREB binding protein (CBP) was first identified as a protein that specifically bound to the phosphorylated form of cyclic-AMP response element binding protein (CREB) [31]. CBP is a coactivator that possesses acetyltransferase activity towards many chromatin-related proteins [32]. CBP can directly bind to NRF2 and synergistically activate ARE [33]. Zhang and colleagues demonstrated that CBP binds to the Neh4 and Neh5 domains of NRF2 and acetylates multiple lysine residues in the Neh1 domain [34

RXRα binds to the Neh7 domain of NRF2

Retinoids are natural and synthetic derivatives of vitamin A and have been used as chemopreventive and chemotherapeutic agents [42]. The effects of retinoids are mediated by specific nuclear receptors, namely retinoic acid receptors (RARα, RARβ, and RARγ) and retinoid X receptors (RXRα, RXRβ, and RXRγ), which are all encoded by different genes [43]. RARs bind to retinoic acid response elements (RAREs) by forming heterodimers with RXRs or other nuclear hormone receptors [44]. Wolf and colleagues

β-TrCP binds to the Neh6 domain of NRF2

Mitogen-activated protein kinases (MAPKs) and the PI3K/AKT signaling pathway can regulate the activity and/or stability of NRF2 [66]. While the underlying mechanisms underlying how MAPK pathways control NRF2/ARE are unclear, a possible culprit kinase that relays the activation of the PI3K/AKT pathway to the stability of NRF2 is glycogen synthase kinase-3β (GSK3β). GSK3β is a downstream kinase of the PI3K/AKT pathway, and it is active when not phosphorylated at Ser9. But the activation of the

Small MAFs bind to the Neh1 domain of NRF2

MAFs are transcription factors that were first identified from the viral oncogene, v-MAF [73]. MAFs can form homodimers and are divided into two groups (large MAFs and small MAFs) depending on their size [74]. Large MAFs (v-MAF, c-MAF, MAFA, MAFB, and NRL) contain a transactivation domain in their N-terminal region, an extended homology region (EHR) in the middle, and a bZIP domain in their C-terminal region (Fig. 3). Large MAFs can form homodimers and activate the transcription of target genes

CHD6 binds to the Neh3 domain of NRF2

Helicases are molecular motor proteins that separate double-stranded nucleic acids using the free energy generated from nucleoside triphosphate (NTP) hydrolysis during translocation on single-stranded (ss) nucleic acid [83]. They were first identified in Escherichia coli in 1976 [84]. Helicases can be grouped into distinct classes depending on (1) the polarity of their nucleic acid unwinding (5′-to-3′ direction or 3′-to-5′ direction), (2) their preferred nucleic acid substrate (DNA or RNA), or

Conclusion

This review described the direct binding partners of NRF2 and their roles in regulating the stability or activity of NRF2. On the other hand, direct binding partners of KEAP1 have been identified. One notable aspect is that many KEAP1 binding proteins competitively interfere with the interaction between NRF2 and KEAP1. One example of this involves p62, also known as sequestosome 1 (SQSTM1), an ubiquitin binding protein that targets protein aggregates for autophagy [90]. Because the STGE motif

Acknowledgments

This work was supported by grants from the National Research Foundation of Korea grant funded by the Korea government (NRF 2018R1A5A2023127) and the Gyeonggi Regional Research Center Program of Gyeonggi Province(GRRC 2017-B01).

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