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International Journal of Molecular Sciences Review NRF2, a Transcription Factor for Stress Response and Beyond 1, , 2, 3, Feng He y * , Xiaoli Ru y and Tao Wen * 1 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA 2 Department of Gynecology and Obstetrics, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; [email protected] 3 Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China * Correspondence: [email protected] (F.H.); [email protected] (T.W.); Tel.: +1-405-496-1762 (F.H.); +86-10-85231557 (T.W.) These authors contributed equally to this work. y Received: 16 June 2020; Accepted: 3 July 2020; Published: 6 July 2020 Abstract: Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of genes involved in oxidative stress response and drug detoxification. NRF2 activation renders cells resistant to chemical carcinogens and inflammatory challenges. In addition to antioxidant responses, NRF2 is involved in many other cellular processes, including metabolism and inflammation, and its functions are beyond the originally envisioned. NRF2 activity is tightly regulated through a complex transcriptional and post-translational network that enables it to orchestrate the cell’s response and adaptation to various pathological stressors for the homeostasis maintenance. Elevated or decreased NRF2 activity by pharmacological and genetic manipulations of NRF2 activation is associated with many metabolism- or inflammation-related diseases. Emerging evidence shows that NRF2 lies at the center of a complex regulatory network and establishes NRF2 as a truly pleiotropic transcription factor. Here we summarize the complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity. Keywords: NRF2; metabolism; UPR; oxidative stress; inflammation; autophagy; proteostasis; transcription factor 1. Introduction Homeostasis is key to organismal health and survival. Environmental stress is ubiquitous and unavoidable to all living beings and threatens to disrupt cell functions. Organisms respond and adapt to stresses through defined regulatory mechanisms. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is best known as one of the main orchestrators of the cellular xenobiotic and oxidative stress response. NRF2, encoded by the gene nuclear factor, erythroid 2 like 2 (NFE2L2), belongs to the Cap’n’Collar (CNC) subfamily of basic leucine zipper (bZIP) transcription factors, which comprises nuclear factor erythroid-derived 2 (NFE2) and NRF1, NRF2, and NRF3 [1]. NRF2 possesses seven conserved NRF2-ECH homology (Neh) domains with different functions to control NRF2 transcriptional activity (Figure1A). 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 Int. J. Mol. Sci. 2020, 21, 4777; doi:10.3390/ijms21134777 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 4777 2 of 23 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 24 Kelch-like-ECH-associated protein 1 (KEAP1) to mediate NRF2 ubiquitination and degradation [2].(Figure The1 B)Neh3-5 [ 2]. Thedomains Neh3-5 function domains as function transcriptional as transcriptional activation activationdomains by domains binding by to binding various to componentsvarious components of the transcriptional of the transcriptional machinery machinery [3]. [Neh63]. Neh6 domain domain contains contains two two redox-independent redox-independent degronsdegrons DSGIS DSGIS and and DSAPGS DSAPGS that that bind bind to to E3 E3 ubiquitin ubiquitin ligase ligase β-transducinβ-transducin repeat-containing repeat-containing protein protein (βTrCP),(βTrCP), whichwhich mediatesmediates NRF2 NRF2 degradation degradation in oxidativelyin oxidatively stressed stressed cells (Figurecells (Figure1C) [ 4 ].1C) Neh7 [4]. domain Neh7 domainmediates mediates interaction interaction with retinoic with Xretinoic receptor X alphareceptor (RXR alphaα), which(RXRα), represses which represses NRF2 activity NRF2 [5 ].activity These [5].domains These modulate domains NRF2modulate stability NRF2 and stability transcriptional and transcriptional activation of itsactivation target genes of its at target multiple genes levels, at multipleincluding levels, transcriptional including andtranscriptional post-transcriptional and post-transcriptional and post-translational and post-translational regulation in response regulation to invarious response insults. to various Recent insults. studies Recent have identifiedstudies have new identified NRF2 target new NRF2 genes target and revealed genes and several revealed new severalfunctions new of NRF2functions that of go NRF2 beyond that its go redox-regulating beyond its redox-regulating capacities, including capacities, regulation including of inflammation, regulation ofautophagy, inflammation, metabolism, autophagy, proteostasis, metabolism, and unfolded proteostasis, protein responseand unfolded (UPR), protein particularly response in the context(UPR), particularlyof carcinogenesis. in the context NRF2 hasof carcinogenesis. become a prime NRF2 subject has of become extensive a prime research subject involving of extensive inflammation, research involvingmetabolism, inflammation, cancer prevention metabolism, and treatment, cancer prevention and its functions and treatment, are more and far-reaching its functions than originallyare more far-reachingenvisioned. Understandingthan originally envisioned. the regulation Understanding of NRF2 activity the andregulation its new of emerging NRF2 activity functions and presentsits new emergingnew challenges functions but presents also new new opportunities challenges for but targeting also new NRF2 opportunities in cancer. for targeting NRF2 in cancer. FigureFigure 1. 1.The architectureThe architecture of Nuclear of factor Nuclear erythroid factor 2-related erythroid factor 2-related 2 (NRF2), factor Kelch-like-ECH- 2 (NRF2), associatedKelch-like-ECH-associated protein 1 (KEAP1), protein and β-transducin 1 (KEAP1), repeat-containing and β-transducin protein repeat-containing (βTrCP). (A protein) NRF2 contains (βTrCP). seven(A) NRF2 conserved contains NRF2-ECH seven conserved homology NRF2-ECH NRF2-ECH homology homology NRF2-ECH (Neh) domains, homology Neh1-Neh7. (Neh) domains, Neh1 containsNeh1-Neh7. a basic Neh1 leucine contains zipper a basic (bZip) leucine motif, zipper where (bZip) the motif,basic region where theis responsible basic region for is responsibleDNA binding for andDNA the binding Zip dimerizes and the Zipwith dimerizes other binding with other partners binding such partners as sMAFs. such Neh2 as sMAFs. contains Neh2 ETGE contains and ETGEDLG motifs,and DLG which motifs, are which required are required for the for interaction the interaction with with KEAP1 KEAP1 and and subsequent subsequent KEAP1-mediated KEAP1-mediated proteasomalproteasomal degradation. degradation. Neh3, Neh3, 4 4 and and 5 5 domains domains are are transactivation transactivation domains domains of of NRF2. Neh4 Neh4 and and 5 5 domainsdomains also also interact interact with with HRD1 HRD1 that that mediates mediates NRF2 NRF2 degradation. degradation. Neh6 Neh6 contains contains two two βTrCPβTrCP degrons degrons DSGISDSGIS and DSAPGSDSAPGS that that are are responsible responsible for thefor βthe-TrCP β-TrCP mediated mediated proteasomal proteasomal degradation. degradation. (B) KEAP1 (B) KEAP1contains contains five domains, five domains, amino amino terminal terminal region region (NTR), (NTR), a broad a broad complex, complex, tramtrack, tramtrack, bric-a-brac bric-a-brac (BTB) (BTB)domain, domain, an intervening an intervening region region (IVR), (IVR), six Kelch six Kelch domains, domains, and the and C-terminal the C-terminal region region (CTR). (CTR). The Kelch The Kelchdomain domain and CTR and mediate CTR mediate the interaction the interaction with NRF2, with NRF2, p62, DPP3, p62, DPP3, WTX, WTX, and PALB2 and PALB2 that contains that contains ETGE ETGEmotifs. motifs. The BTB The domain BTB domain homodimerizes homodimerizes with KEAP1with KEAP1 and contributes and contributes to the to interaction the interaction of IVR of withIVR withCul3 Cul3/RBX1/RBX1 complex. complex. Several Several functional functional important important cysteine cysteine residues residues (C151, (C151, C226, C226, C273 C273 and and C278) C278) that thatsense sense reactive reactive oxygen oxygen species species (ROS) (ROS) and electrophilesand electrophiles and modulate and modulate KEAP1-NRF2 KEAP1-NRF2 interaction. (C) βTrCP has three domains, dimerization domain (D) that forms homo- and heterodimers between βTrCP1 and βTrCP2, the F-box that recruits SKP1 for the binding of CUL1/RBX1 complex, and the WD40 repeat domain that binds βTrCP degrons DSGIS and DSAPGS in NRF2. βTrCP, β-transducing repeat-containing protein; CUL3, Cullin3; RBX1, RING-box protein; WD40, WD Repeat protein 40; RXRα, retinoic X receptor alpha; DPP3, dipeptidyl peptidase 3; WTX, Wilms tumor
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