NFE2L2

This gene encodes a transcription factor which is a member of a small family of basic leucine zipper (bZIP) proteins. The encoded transcription factor regulates genes which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to injury and inflammation which includes the production of free radicals. Multiple transcript variants encoding different isoforms have been characterized for this gene.

NFE2L2

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).

Plays also 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).

Aflatoxin catabolic process Source: Ensembl
Aging Source: Ensembl
Cell redox homeostasis Source: UniProtKB
Cellular response to angiotensin Source: Ensembl
Cellular response to copper ion Source: Ensembl
Cellular response to fluid shear stress Source: UniProtKB
Cellular response to glucose starvation Source: Ensembl
Cellular response to hydrogen peroxide Source: BHF-UCL
Cellular response to laminar fluid shear stress Source: BHF-UCL
Cellular response to oxidative stress Source: UniProtKB
Cellular response to tumor necrosis factor Source: BHF-UCL
Cellular response to xenobiotic stimulus Source: Ensembl
Endoplasmic reticulum unfolded protein response Source: ParkinsonsUK-UCL
Inflammatory response Source: Ensembl
Integrated stress response signaling Source: ComplexPortal
Negative regulation of cardiac muscle cell apoptotic process Source: Ensembl
Negative regulation of endothelial cell apoptotic process Source: BHF-UCL
Negative regulation of hematopoietic stem cell differentiation Source: Ensembl
Negative regulation of hydrogen peroxide-induced cell death Source: ParkinsonsUK-UCL
Negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway Source: BHF-UCL
Negative regulation of vascular associated smooth muscle cell migration Source: Ensembl
PERK-mediated unfolded protein response Source: ParkinsonsUK-UCL
Positive regulation of angiogenesis Source: Ensembl
Positive regulation of blood coagulation Source: Ensembl
Positive regulation of blood vessel endothelial cell migration Source: Ensembl
Positive regulation of ER-associated ubiquitin-dependent protein catabolic process Source: ParkinsonsUK-UCL
Positive regulation of gene expression Source: CACAO
Positive regulation of glucose import Source: Ensembl
Positive regulation of glutathione biosynthetic process Source: Ensembl
Positive regulation of neuron projection development Source: Ensembl
Positive regulation of reactive oxygen species metabolic process Source: Ensembl
Positive regulation of transcription by RNA polymerase II Source: ParkinsonsUK-UCL
Positive regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: BHF-UCL
Positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: Ensembl
Positive regulation of transcription from RNA polymerase II promoter in response to stress Source: BHF-UCL
Proteasomal ubiquitin-independent protein catabolic process Source: UniProtKB
Proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
Protein ubiquitination Source: UniProtKB
Regulation of embryonic development Source: Ensembl
Regulation of innate immune response Source: UniProtKB
Regulation of removal of superoxide radicals Source: Ensembl
Regulation of transcription by RNA polymerase II Source: GO_Central
Response to lithium ion Source: Ensembl

Nucleus
cytosol
Note: Cytosolic under unstressed conditions: ubiquitinated and degraded by the BCR(KEAP1) E3 ubiquitin ligase complex (PubMed:15601839, PubMed:21196497). Translocates into the nucleus upon induction by electrophilic agents that inactivate the BCR(KEAP1) E3 ubiquitin ligase complex (PubMed:21196497).

Immunodeficiency, developmental delay, and hypohomocysteinemia (IMDDHH):
An early onset multisystem disorder characterized by immunodeficiency, recurrent infections, developmental delay, poor growth, intellectual disability, and hypohomocysteinemia. Some patients manifest congenital cardiac defects. IMDDHH inheritance pattern is autosomal dominant.

Ubiquitinated in the cytoplasm by the BCR(KEAP1) E3 ubiquitin ligase complex leading to its degradation (PubMed:15601839, PubMed:15983046, PubMed:19489739). In response to oxidative stress, electrophile metabolites, such as sulforaphane, modify KEAP1, leading to inhibit activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and activity (PubMed:19489739, PubMed:29590092). In response to autophagy, the BCR(KEAP1) complex is inactivated (By similarity).
Phosphorylation of Ser-40 by PKC in response to oxidative stress dissociates NFE2L2 from its cytoplasmic inhibitor KEAP1, promoting its translocation into the nucleus.
Acetylation at Lys-596 and Lys-599 increases nuclear localization whereas deacetylation by SIRT1 enhances cytoplasmic presence.
Glycation impairs transcription factor activity by preventing heterodimerization with small Maf proteins (PubMed:31398338). Deglycation by FN3K restores activity (PubMed:31398338).