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.
Highlights
Homeostasis is key to organismal health and survival
The NFE2L2 gene contains one xenobiotic-responsive element (XRE)-like element at position -712 of the promoter region and two additional XRE-like elements located at +755 and +850 that are activated by the transcription factor aryl hydrocarbon receptor (AHR) [30]
nuclear factor erythroid 2-related factor 2 (NRF2) is best known as an oxidant stress response transcription factor, it is critical to the regulation of metabolism, inflammation, autophagy, proteostasis, mitochondrial physiology, and immune responses
Summary
Homeostasis is key to organismal health and survival. Environmental stress is ubiquitous and unavoidable to all living beings and threatens to disrupt cell functions. The bZip in the Neh 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 Neh domain contains ETGE and DLG motifs that interact with Kelch domain of. ΒTrCP, β-transducing repeat-containing protein; CUL3, Cullin; RBX1, RING-box protein; WD40, WD Repeat protein 40; RXRα, retinoic X receptor alpha; DPP3, dipeptidyl peptidase 3; WTX, Wilms tumor gene on X. ΒTrCP, β-transducing repeat-containing protein; CUL3, Cullin; RBX1, RING-box protein; WD40, WD Repeat protein 40; RXRα, retinoic X receptor alpha; DPP3, dipeptidyl peptidase 3; WTX, Wilms tumor gene on X chromosome; PALB2, Partner and Localizer of BRCA2; GSK3, Glycogen synthase kinase-3; SKP1, S-phase kinase-associated protein-1 Sci. 2020, 21, 4777 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, Cullin; RBX1, RING-box protein; WD40, WD Repeat protein 40; RXRα, retinoic X receptor alpha; DPP3, dipeptidyl peptidase 3; WTX, Wilms tumor gene on X chromosome; PALB2, Partner and Localizer of BRCA2; GSK3, Glycogen synthase kinase-3; SKP1, S-phase kinase-associated protein-1
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