NFE2L2 Protein, Human (His)

NFE2L2, a pivotal transcription factor, assumes a central role in the cellular response to oxidative stress. It binds to antioxidant response elements (ARE) in the promoter regions of numerous cytoprotective genes, including phase 2 detoxifying enzymes, promoting their expression and neutralizing reactive electrophiles. Under normal conditions, NFE2L2 is ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex. However, in the face of oxidative stress, electrophile metabolites inhibit the BCR(KEAP1) complex, leading to nuclear accumulation of NFE2L2, heterodimerization with small Maf proteins, and binding to ARE elements in cytoprotective target genes. The NFE2L2/NRF2 pathway is also activated in response to selective autophagy, where autophagy facilitates the interaction between KEAP1 and SQSTM1/p62, inactivating the BCR(KEAP1) complex and allowing for NFE2L2 nuclear accumulation. Apart from its role in oxidative stress response, NFE2L2 contributes to the transcriptional activation of genes in the beta-globin cluster and plays a critical role in regulating the innate immune response and antiviral cytosolic DNA sensing. It acts as a key regulator during sepsis, maintaining redox homeostasis and restraining dysregulation in pro-inflammatory signaling pathways. Furthermore, NFE2L2 suppresses the macrophage inflammatory response, inhibiting pro-inflammatory cytokine transcription and the induction of IL6. It also represses antiviral cytosolic DNA sensing by suppressing the expression of the adapter protein STING1, limiting the release of pro-inflammatory cytokines in response to human coronavirus SARS-CoV-2 infection and other pathogenic viruses. Activation of NFE2L2 is facilitated by cell-derived metabolites, including itaconate and fumarate.