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Review
. 2016 Sep;73(17):3221-47.
doi: 10.1007/s00018-016-2223-0. Epub 2016 Apr 21.

Role of Nrf2/HO-1 System in Development, Oxidative Stress Response and Diseases: An Evolutionarily Conserved Mechanism

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Free PMC article
Review

Role of Nrf2/HO-1 System in Development, Oxidative Stress Response and Diseases: An Evolutionarily Conserved Mechanism

Agnieszka Loboda et al. Cell Mol Life Sci. .
Free PMC article

Abstract

The multifunctional regulator nuclear factor erythroid 2-related factor (Nrf2) is considered not only as a cytoprotective factor regulating the expression of genes coding for anti-oxidant, anti-inflammatory and detoxifying proteins, but it is also a powerful modulator of species longevity. The vertebrate Nrf2 belongs to Cap 'n' Collar (Cnc) bZIP family of transcription factors and shares a high homology with SKN-1 from Caenorhabditis elegans or CncC found in Drosophila melanogaster. The major characteristics of Nrf2 are to some extent mimicked by Nrf2-dependent genes and their proteins including heme oxygenase-1 (HO-1), which besides removing toxic heme, produces biliverdin, iron ions and carbon monoxide. HO-1 and their products exert beneficial effects through the protection against oxidative injury, regulation of apoptosis, modulation of inflammation as well as contribution to angiogenesis. On the other hand, the disturbances in the proper HO-1 level are associated with the pathogenesis of some age-dependent disorders, including neurodegeneration, cancer or macular degeneration. This review summarizes our knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors.

Keywords: Heme oxygenase-1 (HO-1); Kelch-like ECH-associated protein 1 (Keap1); Nuclear factor erythroid 2-related factor 2 (Nrf2); Oxidative stress; Reactive oxygen species (ROS).

Figures

Fig. 1
Fig. 1
Schematic representation of the Nrf2-Keap1 pathway. Under normal conditions, Nrf2 is sequestered in cytoplasm by Keap1. In stressful conditions the modification of –SH groups in Keap1 or phosphorylation of Nrf2 facilitate the dissociation of Nrf2 from Keap1 as well as translocation of Nrf2 into the nucleus. After binding Maf proteins, Nrf2 activates antioxidant response element (ARE) and increases transcription of Nrf2-regulated genes (e.g., HO-1, GST, NQO-1)
Fig. 2
Fig. 2
Complexity of CNC transcription factors and Keap1 regulator. CNC family of transcription factors share a high homology between D. melanogaster, C. elegans and Homo sapiens. From three Nrf factors found in vertebrates, the detailed domain structure of Nrf2 is shown. In C. elegans, three isoforms of SKN-1 factor possessing CNC domain responsible for DNA binding have been identified. In D. melanogaster CncA, CncB and CncC have distinct N-terminal end, but share very homologous C-terminus harboring the bZIP (a). Mammalian Keap1 consists of several domains which contain crucial cysteine residues. In zebrafish, two types of Keap1 with high homology to mammalian Keap1 are identified (similarity in amino acid sequences between zebrafish and mouse Keap1 shown in percentage). Keap1a and Keap1b, differ in the presence of essential Cys273 and Cys288, whereas dKeap1 in Drosophila lacks other cysteines but possess Cys273 and Cys288. In nematode, the function of negative regulator of SKN-1 is played by WDR-23 (b)
Fig. 3
Fig. 3
The role of SKN-1 in the development of C. elegans. In the early embryo skn-1 mRNA is deposited in both cells: AB and P1, but the level of SKN-1 protein is higher in the posterior cell (P1). This asymmetry is regulated by EEL-1, which binds SKN-1 and targets it to degradation mainly in AB cell. After division AB cell forms Aba (anterior) and ABp (posterior) cells and P1 forms P2 and EMS cells. In this four-cell embryo, SKN-1 is concentrated mostly in EMS cell. In the next step, EMS divides into the mesodermal MS precursor, which develop into pharynx and muscles, and the endodermal E precursor, which generates intestine cells. SKN-1 increases level of the transcription factors MED-1 and MED-2, which in turn activates end-1,3 transcription. In MS cell POP-1 protein inhibits END-1,3, whereas MED-1 and MED-2 activate transcription factors: tbx-35 and ceh-51, which are crucial for mesoderm development. In E cell POP-1 is modified on Wnt/β-catenin-dependent pathway, what activates END-1,3. END-1,3 cooperate with each other to increase the level of ELT-2, which starts intestine development
Fig. 4
Fig. 4
Cnc factors regulate development of D. melanogaster. Maternally deposited Cnc has important functions in egg polarization. In embryo Cnc is concentrated in the anterior part, in “cap” and “collar” domains. Cnc co-operates with Dfd in tissue development. In cells which express both Cnc and Dfd, Cnc forms heterodimers with MafS protein, and inhibits Dfd function. As the result, mandibular structures develop. Cells expressing only Dfd develop into maxillary structures. Finally, cell expressing Cnc only form pharynx structures
Fig. 5
Fig. 5
Heme oxygenase-1 pathway. HO-1, and inducible enzyme, cooperating with NADPH cytochrome P450 degrades heme to produce three bioactive products: iron ions, carbon monoxide and biliverdin, which is rapidly converted to bilirubin, through the action of biliverdin reductase (BVR). Tissue protection is exerted by the activity of all products and their functioning as a pro-angiogenic, antioxidant or anti-inflammatory factors
Fig. 6
Fig. 6
Nrf2 activity decreases with aging. Age-related changes in the Nrf2 regulatory system, including increase in Bach1 and Keap1 lead to the inhibition of Nrf2 activity and downstream effects
Fig. 7
Fig. 7
CncC/SKN-1/Nrf2 involvement in the regulation of proteasome. The Nrf2-dependent up-regulation of the proteasome levels, assembly, and activity may result in the adaptation to stressful conditions, lifespan extension and increased resistance to stress. The regulation of proteasome genes (Rpn1, Beta-2, 20S, p97) is indicated
Fig. 8
Fig. 8
Neuroprotective activity of Nrf2. Nrf2 mediates neuroprotection through several possible mechanisms. The reduction of oxidative stress, modulation of inflammation as well as autophagy process may contribute to protective effects of Nrf2 in the nervous system. Of note, p62 may directly activate Nrf2 through sequestration of Keap1
Fig. 9
Fig. 9
Age-related macular degeneration and Nrf2. Decrease in Nrf2 and increase in Keap1 levels as well as Nrf2 and HO-1 promoter polymorphism contribute to damage of the retinal pigment epithelium (RPE) cells and photoreceptors. Nrf2 deficiency leads to increased oxidative stress and deregulated autophagy magnified the accumulation of protein aggregates and drusen formation
Fig. 10
Fig. 10
Role of Nrf2/HO-1 in tumor initiation and progression. Both Nrf2 and HO-1 may decrease tumor initiation through the detoxification and ROS scavenging mechanisms. On the other hand, this cytoprotective system exerts stimulatory effect on the progression of tumors mostly due to its anti-apoptotic, pro-angiogenic, pro-migratory and modulatory influence on the expression of microRNAs. However, in some tumors the opposite, inhibitory effect on progression of tumors have been reported
Fig. 11
Fig. 11
miRNAs biogenesis and their role in the regulation of Nrf2 expression. microRNAs, transcribed by polymerase II as pri-miRNAs, are cleaved by endoribonucleases Drosha and DGCR8, to be finally exported from the nucleus by exportin-5. An endoribonuclease Dicer processes the pre-miRNA, creating a mature, double-stranded miRNA duplex. Endogenous miRNAs bind to target sequences in the 3′UTR regions of their target mRNA to produce translational arrest. Some miRNAs, e.g., miR-200a can target Keap1 mRNA, leading to its degradation and up-regulation of Nrf2 targets. On the other hand, miR-144 can affect Nrf2 level in a Keap1-independent manner but through direct targeting the 3′UTR of Nrf2 mRNA causing the down-regulation in Nrf2 expression

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