Introduction About Nrf2 (NFE2L2): A Drug Target (G4780)

NCBI ID: G4780

NFE2L2

Introduction About Nrf2 (NFE2L2): A Drug Target

Nrf2 is regulated by multiple epigenetic mechanisms, including DNA methylation, histone acetylation, and histone methylation. Understanding these regulatory mechanisms is crucial for exploring potential modulators of Nrf2 signaling at different levels of gene expression.

Genes associated with the NRF2-mediated oxidative stress response pathway show differential regulation in conditions like aldosterone-producing adenoma (APA) and different zones of the adrenal cortex.

Nrf2 plays a role in the saccular-to-alveolar transition in the lung and participates in cellular processes such as antioxidant protection, cell cycle regulation, DNA repair, and mitochondria-related metabolism. Nrf2 deficiency can disrupt these processes and activate inflammatory signaling, potentially leading to lung injury and conditions like bronchopulmonary dysplasia (BPD).

The turnover pathway involving the Keap1/Cul3/Rbx1 complex is not the sole mechanism regulating Nrf2 during RV infection. Additional noncanonical regulatory networks are involved in downregulating the Nrf2/HO-1 axis after the initial hours of infection.

The activity of Nrf2 is primarily regulated through its association with the E3 ubiquitin ligase KEAP1. Reactive oxygen species and alkylating compounds can disrupt the KEAP1-Nrf2 complex, leading to Nrf2 translocation to the nucleus and the expression of genes involved in oxidative stress resistance. The inhibition of Nrf2 has also been reported.

These viewpoints demonstrate that Nrf2 is a critical regulator of oxidative stress response and cellular processes in various tissues, and its dysregulation can contribute to pathological conditions. Researchers are interested in understanding the epigenetic regulation of Nrf2, identifying modulators of Nrf2 signaling, and exploring its association with diseases like BPD and cancer drug resistance.
Based on the provided context information, here is a key viewpoint about Nrf2 (synonymous with NFE2L2):

NRF2 activation: Nrf2 can be activated by inhibiting GSK3beta, which promotes Nrf2 phosphorylation, nuclear exit, and degradation, resulting in reduced antioxidant gene expression and response. On the other hand, aberrant NRF2 activation in cancer cells confers resistance to anticancer drugs and radiation.

Furthermore, some additional viewpoints about Nrf2 can be inferred from the context:

Role in antioxidant defense: NRF2 plays a crucial role in antioxidant defense by regulating the expression of SLC7A11, which enhances antioxidant defense through glutathione synthesis. NRF2 also contributes to the antioxidant function and detoxification in normal quiescent cells.

Role in metabolism: In addition to its antioxidant function, NRF2 contributes to metabolic reprogramming in proliferating cells, facilitating the pentose phosphate pathway and serine synthesis.

Autophagy and Nrf2 activation: Impaired autophagy can lead to accumulation of p62, which sequesters Keap1, resulting in the release of Nrf2 and increased antioxidant capacity.

These viewpoints showcase the various roles and implications of Nrf2 activation in cellular processes such as antioxidant defense, metabolism, and cancer cell resistance.

Protein Name: NFE2 Like BZIP Transcription Factor 2

Functions: Transcription factor that plays a key role in the response to oxidative stress: binds to antioxidant response (ARE) elements present in the promoter region of many cytoprotective genes, such as phase 2 detoxifying enzymes, and promotes their expression, thereby neutralizing reactive electrophiles (PubMed:11035812, PubMed:19489739, PubMed:29018201, PubMed:31398338). In normal conditions, ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex (PubMed:11035812, PubMed:15601839, PubMed:29018201). In response to oxidative stress, electrophile metabolites inhibit activity of the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2, heterodimerization with one of the small Maf proteins and binding to ARE elements of cytoprotective target genes (PubMed:19489739, PubMed:29590092). The NFE2L2/NRF2 pathway is also activated in response to selective autophagy: autophagy promotes interaction between KEAP1 and SQSTM1/p62 and subsequent inactivation of the BCR(KEAP1) complex, leading to NFE2L2/NRF2 nuclear accumulation and expression of cytoprotective genes (PubMed:20452972). May also be involved in the transcriptional activation of genes of the beta-globin cluster by mediating enhancer activity of hypersensitive site 2 of the beta-globin locus control region (PubMed:7937919). Also plays an important role in the regulation of the innate immune response and antiviral cytosolic DNA sensing. It is a critical regulator of the innate immune response and survival during sepsis by maintaining redox homeostasis and restraint of the dysregulation of pro-inflammatory signaling pathways like MyD88-dependent and -independent and TNF-alpha signaling (By similarity). Suppresses macrophage inflammatory response by blocking pro-inflammatory cytokine transcription and the induction of IL6 (By similarity). Binds to the proximity of pro-inflammatory genes in macrophages and inhibits RNA Pol II recruitment. The inhibition is independent of the NRF2-binding motif and reactive oxygen species level (By similarity). Represses antiviral cytosolic DNA sensing by suppressing the expression of the adapter protein STING1 and decreasing responsiveness to STING1 agonists while increasing susceptibility to infection with DNA viruses (PubMed:30158636). Once activated, limits the release of pro-inflammatory cytokines in response to human coronavirus SARS-CoV-2 infection and to virus-derived ligands through a mechanism that involves inhibition of IRF3 dimerization. Also inhibits both SARS-CoV-2 replication, as well as the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism (PubMed:33009401)

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•   general information;
•   protein structure and compound binding;
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•   expression level;
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