NFE2L2 (Nuclear factor erythroid 2-related factor 2, also known as NRF2) is the master transcription factor regulating cellular antioxidant and cytoprotective responses. As a CNC-bZIP family member, NRF2 heterodimerizes with small MAF proteins (MAFG, MAFK, MAFF) to bind antioxidant response elements (AREs) in the promoters of target genes including phase II detoxifying enzymes (NQO1, GSTA), glutathione synthesis genes (GCLC, GCLM), heme oxygenase (HMOX1), and the cystine/glutamate antiporter SLC7A11. Under basal conditions, NRF2 is sequestered in the cytoplasm by KEAP1, which serves as a substrate adaptor for the CUL3-RBX1 E3 ubiquitin ligase complex, targeting NRF2 for proteasomal degradation with a half-life of approximately 15 minutes. Upon oxidative stress or electrophile exposure, reactive KEAP1 cysteines are modified, disrupting NRF2 ubiquitination and allowing newly synthesized NRF2 to accumulate in the nucleus. NRF2 also plays a critical role in protection against ferroptosis by inducing genes that maintain iron and lipid homeostasis. Constitutive NRF2 activation via somatic mutations in NFE2L2 or KEAP1 is common in lung cancers and promotes tumor progression and therapy resistance.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: NRF2 contains a bZIP DNA-binding domain (residues 497-560) that enables sequence-specific binding to antioxidant response elements (AREs). This molecular function is well-established through structural studies (PMID:16888629) and ChIP experiments (PMID:20452972). Reason: This is a core molecular function of NRF2 as a bZIP transcription factor. The phylogenetic inference is sound and supported by extensive experimental evidence across species. Supporting Evidence: PMID:20452972 2010 May 7. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. file:human/NFE2L2/NFE2L2-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: NRF2 is the prototypical ARE-binding transcription factor that activates Pol II-mediated transcription of cytoprotective genes upon nuclear translocation. Reason: This is a core molecular function representing NRF2's ability to activate transcription upon DNA binding. Well-supported by IBA phylogenetic inference and experimental data. Supporting Evidence: PMID:20452972 2010 May 7. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: NRF2 translocates to the nucleus upon stabilization (following electrophile exposure or autophagy-mediated KEAP1 sequestration) where it binds AREs and activates transcription. Reason: Nuclear localization is essential for NRF2's transcription factor function. Under stress conditions, NRF2 accumulates in the nucleus to exert its transcriptional activity. Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: NRF2 is a master regulator of transcription, activating hundreds of genes containing AREs in their regulatory regions upon oxidative or electrophilic stress. Reason: This biological process is the primary function of NRF2. The IBA annotation captures the conserved regulatory role across species. Supporting Evidence: PMID:20452972 2010 May 7. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. |
| GO:0034599 cellular response to oxidative stress | IBA GO_REF:0000033 | ACCEPT | Summary: NRF2 is THE master regulator of the cellular oxidative stress response. Upon oxidative stress, KEAP1 cysteine sensors are modified, preventing NRF2 degradation and enabling transcription of antioxidant genes. Reason: This is the defining biological process for NRF2 function. The KEAP1-NRF2 pathway is the primary sensor and effector system for oxidative and electrophilic stress responses. Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. PMID:26403645 Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of IBA annotation. Automated inference from ortholog and InterPro data confirms the DNA-binding function. Reason: Consistent with IBA annotation and well-supported by NRF2's bZIP domain structure. |
| GO:0003677 DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: General DNA binding term inferred from InterPro bZIP domain annotations. Reason: While more general than sequence-specific DNA binding, this is a valid annotation for the bZIP domain-containing NRF2. The IBA annotation for sequence-specific binding is more informative. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Inferred from bZIP domain annotations. NRF2 is a classic DNA-binding transcription factor. Reason: Core molecular function of NRF2, well-established through domain analysis and experimental evidence. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Automated inference of nuclear localization from orthologs and subcellular location data. Reason: Consistent with IBA and experimental IDA annotations. Nuclear localization is essential for NRF2 transcription factor function. |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: NRF2 is cytosolic when bound to KEAP1 under basal conditions. Reason: Accurate annotation. Under normal conditions, KEAP1 sequesters NRF2 in the cytosol for ubiquitin-mediated degradation. |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | ACCEPT | Summary: Inferred from UniProt keyword mapping. NRF2 is involved in transcription. Reason: Valid general annotation. More specific annotations about transcription regulation are also present. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000120 | ACCEPT | Summary: Inferred from InterPro bZIP domain annotations. Reason: NRF2 is a transcriptional activator. This general term is appropriate given the more specific IBA annotation for Pol II regulation. |
| GO:0006357 regulation of transcription by RNA polymerase II | IEA GO_REF:0000002 | ACCEPT | Summary: Inferred from InterPro NFE2-like family annotation. Reason: Consistent with IBA annotation for this process. NRF2 specifically regulates Pol II transcription. |
| GO:0005515 protein binding | IPI PMID:16888629 Structure of the Keap1:Nrf2 interface provides mechanistic i... | MODIFY | Summary: Structural study demonstrating NRF2 ETGE peptide binding to KEAP1 Kelch domain. This shows specific interaction with KEAP1 (Q14145). Reason: While the interaction with KEAP1 is well-documented, 'protein binding' is too general and uninformative. The annotation should capture the specific nature of this E3 ligase substrate-adaptor interaction. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:16888629 Aug 3. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. |
| GO:0005515 protein binding | IPI PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, ... | MARK AS OVER ANNOTATED | Summary: DJ-1 stabilizes NRF2 by preventing KEAP1-mediated degradation. Shows interaction with both KEAP1 (Q14145) in the context of NRF2 stabilization. Reason: The publication focuses on DJ-1 stabilizing NRF2, but the protein binding annotation is with KEAP1. This is a valid interaction but 'protein binding' does not capture the regulatory significance. Supporting Evidence: PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. |
| GO:0005515 protein binding | IPI PMID:18048326 Identification of retinoic acid as an inhibitor of transcrip... | MARK AS OVER ANNOTATED | Summary: Retinoic acid receptor alpha (RARA) inhibits NRF2 transcriptional activity. Reason: Interaction with RARA represents a regulatory mechanism, but 'protein binding' is uninformative. Context-specific terms would be more appropriate. Supporting Evidence: PMID:18048326 Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha. |
| GO:0005515 protein binding | IPI PMID:18692475 A protein domain-based interactome network for C. elegans ea... | ACCEPT | Summary: C. elegans interactome study showing interaction with MAFG (O15525). Reason: Interaction with small MAF proteins (MAFG, MAFK, MAFF) is essential for NRF2 DNA binding and transcriptional activation. These are obligate heterodimerization partners. Supporting Evidence: PMID:18692475 A protein domain-based interactome network for C. |
| GO:0005515 protein binding | IPI PMID:18757741 Cancer related mutations in NRF2 impair its recognition by K... | MODIFY | Summary: Cancer-related NRF2 mutations impair KEAP1 recognition. Shows NRF2-KEAP1 interaction. Reason: This is the functionally critical KEAP1 binding that targets NRF2 for degradation. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:18757741 Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. |
| GO:0005515 protein binding | IPI PMID:19706542 Nitric oxide activation of Keap1/Nrf2 signaling in human col... | MARK AS OVER ANNOTATED | Summary: Nitric oxide activation of KEAP1/NRF2 signaling pathway in colon carcinoma cells. Reason: Another KEAP1 interaction study. The regulatory nature is not captured by generic protein binding term. Supporting Evidence: PMID:19706542 Nitric oxide activation of Keap1/Nrf2 signaling in human colon carcinoma cells. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | ACCEPT | Summary: Human liver protein interactome study showing NRF2 interactions with MAFG, MAFK, KEAP1. Reason: High-throughput interactome study confirming known interactions. Small MAF proteins are essential partners. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver. |
| GO:0005515 protein binding | IPI PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... | ACCEPT | Summary: Networks of bZIP protein-protein interactions. Shows NRF2 interactions with MAFG, ATF4, and MAFF. Reason: Interactions with bZIP family members including small MAFs and ATF4 are central to NRF2 function in stress response. Supporting Evidence: PMID:23661758 Networks of bZIP protein-protein interactions diversified over a billion years of evolution. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | ACCEPT | Summary: Proteome-scale human interactome network showing NRF2 interactions. Reason: Large-scale validation of NRF2 protein interactions. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:25684205 CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP ... | MARK AS OVER ANNOTATED | Summary: CUL3-KBTBD6/KBTBD7 ubiquitin ligase study mentioning KEAP1 interactions. Reason: Focus is on CUL3 substrate adaptors; NRF2-KEAP1 interaction is tangential. Supporting Evidence: PMID:25684205 2015 Feb 12. CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP proteins to spatially restrict TIAM1-RAC1 signaling. |
| GO:0005515 protein binding | IPI PMID:26700459 Involvement of Nrf2 in proteasome inhibition-mediated induct... | ACCEPT | Summary: Proteasome inhibition induces NRF2/ATF4 interaction. Reason: ATF4 is a stress-responsive bZIP transcription factor that partners with NRF2 in integrated stress response. Supporting Evidence: PMID:26700459 Involvement of Nrf2 in proteasome inhibition-mediated induction of ORP150 in thyroid cancer cells. |
| GO:0005515 protein binding | IPI PMID:28777872 The short isoform of PML-RARΞ± activates the NRF2/HO-1 pathwa... | ACCEPT | Summary: PML-RARΞ± activates NRF2 through direct interaction. Reason: Shows NRF2 regulation in leukemia context. Supporting Evidence: PMID:28777872 Aug 21. The short isoform of PML-RARΞ± activates the NRF2/HO-1 pathway through a direct interaction with NRF2. |
| GO:0005515 protein binding | IPI PMID:29792731 APR3 modulates oxidative stress and mitochondrial function i... | MARK AS OVER ANNOTATED | Summary: APR3 modulates oxidative stress in retinal epithelial cells through NRF2. Reason: Context-specific interaction that does not define core NRF2 function. Supporting Evidence: PMID:29792731 of print. APR3 modulates oxidative stress and mitochondrial function in ARPE-19 cells. |
| GO:0005515 protein binding | IPI PMID:31169361 A Case Study on the Keap1 Interaction with Peptide Sequence ... | MODIFY | Summary: Peptidomic display study on KEAP1 interaction with NRF2-derived peptides. Reason: This is specifically about the KEAP1 E3 ligase interaction. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:31169361 2019 Jun 6. A Case Study on the Keap1 Interaction with Peptide Sequence Epitopes Selected by the Peptidomic mRNA Display. |
| GO:0005515 protein binding | IPI PMID:31262713 FAM129B, an antioxidative protein, reduces chemosensitivity ... | MODIFY | Summary: FAM129B competes with NRF2 for KEAP1 binding. Reason: Demonstrates the competitive binding to KEAP1 E3 ligase. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:31262713 Jun 28. FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 binding. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: Genetic variants disrupting protein interactions. TNNT1 interaction shown. Reason: Interaction with troponin T (TNNT1) is unlikely to be functionally significant for NRF2's transcription factor role. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | ACCEPT | Summary: Reference map of human binary protein interactome confirming NRF2 interactions with MAFG, MAFK, KDM1A. Reason: Confirms essential interactions with small MAF proteins and histone demethylase KDM1A involved in transcriptional regulation. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32911434 A functionally defined high-density NRF2 interactome reveals... | ACCEPT | Summary: High-density NRF2 interactome identifying conditional regulators of ARE transactivation. This comprehensive study identified many NRF2 interactors including transcription factors, nuclear import proteins, and signaling molecules. Reason: Comprehensive interactome study providing validated NRF2 interaction partners that regulate ARE-driven transcription. Supporting Evidence: PMID:32911434 Aug 20. A functionally defined high-density NRF2 interactome reveals new conditional regulators of ARE transactivation. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | ACCEPT | Summary: Dual proteome-scale networks showing cell-specific NRF2 interactome remodeling. Reason: Shows context-dependent NRF2 interactions with MAFK, MAFF in different cell types. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:34591642 A protein network map of head and neck cancer reveals PIK3CA... | ACCEPT | Summary: Protein network in head and neck cancer showing NRF2 interactions. Reason: Cancer-relevant interaction network confirming NRF2 partners. Supporting Evidence: PMID:34591642 Oct 1. A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity. |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | ACCEPT | Summary: Mutation-directed neo-interactions in cancer. Shows mutant NRF2-KEAP1 interactions. Reason: Important for understanding cancer-specific NRF2 pathway dysregulation. Supporting Evidence: PMID:35512704 2022 May 4. Systematic discovery of mutation-directed neo-protein-protein interactions in cancer. |
| GO:0005515 protein binding | IPI PMID:36442525 ARD1 stabilizes NRF2 through direct interaction and promotes... | ACCEPT | Summary: ARD1 (NAA10) stabilizes NRF2 through direct interaction and promotes colon cancer. Reason: Shows regulatory interaction with NAA10 acetyltransferase affecting NRF2 stability. Supporting Evidence: PMID:36442525 Nov 25. ARD1 stabilizes NRF2 through direct interaction and promotes colon cancer progression. |
| GO:0005515 protein binding | IPI PMID:37187359 Geniposide ameliorates dextran sulfate sodium-induced ulcera... | MARK AS OVER ANNOTATED | Summary: Geniposide ameliorates ulcerative colitis via KEAP1-NRF2 signaling. Reason: Pharmacological study; KEAP1-NRF2 interaction is tangential to main finding. Supporting Evidence: PMID:37187359 2023 May 13. Geniposide ameliorates dextran sulfate sodium-induced ulcerative colitis via KEAP1-Nrf2 signaling pathway. |
| GO:0005515 protein binding | IPI PMID:38891776 Pin1 Downregulation Is Involved in Excess Retinoic Acid-Indu... | ACCEPT | Summary: Pin1 involved in neural tube closure. Shows NRF2-PIN1 interaction. Reason: PIN1 is a peptidyl-prolyl isomerase that can regulate NRF2 activity through conformational changes. Supporting Evidence: PMID:38891776 Pin1 Downregulation Is Involved in Excess Retinoic Acid-Induced Failure of Neural Tube Closure. |
| GO:0005515 protein binding | IPI PMID:39009827 Proteome-scale characterisation of motif-based interactome r... | ACCEPT | Summary: Disease mutations affecting motif-based interactome. KEAP1 interaction affected by NRF2 mutations. Reason: Important for understanding how disease mutations in NRF2 ETGE/DLG motifs disrupt KEAP1 binding. Supporting Evidence: PMID:39009827 2024 Jul 15. Proteome-scale characterisation of motif-based interactome rewiring by disease mutations. |
| GO:0000785 chromatin | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 associates with chromatin at ARE sites to activate transcription. Reason: As a DNA-binding transcription factor, NRF2 must associate with chromatin to exert its function. |
| GO:0000976 transcription cis-regulatory region binding | IEA GO_REF:0000120 | ACCEPT | Summary: NRF2 binds to ARE cis-regulatory elements in target gene promoters. Reason: Well-established molecular function of NRF2. |
| GO:0001221 transcription coregulator binding | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 interacts with coactivators like CBP/p300 to enhance transcription. Reason: NRF2 recruits transcriptional coactivators to AREs for robust gene activation. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 specifically activates Pol II-mediated transcription of target genes. Reason: Core molecular function of NRF2 as a transcriptional activator. |
| GO:0002931 response to ischemia | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NRF2 activation provides cytoprotection during ischemia/reperfusion injury. Reason: Ischemia protection is a downstream consequence of NRF2's antioxidant program rather than a core function. NRF2 is activated by oxidative stress during ischemia. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 is located in the cytoplasm when bound to KEAP1. Reason: Accurate. Under basal conditions, KEAP1 retains NRF2 in the cytoplasm. |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 is activated by xenobiotic electrophiles and induces detoxification genes. Reason: Core function of NRF2. Electrophilic xenobiotics modify KEAP1 cysteines, stabilizing NRF2 to induce phase II detoxifying enzymes. |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000120 | ACCEPT | Summary: NRF2 positively regulates expression of ARE-containing target genes. Reason: Core function as a transcriptional activator. |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NRF2 protects cardiomyocytes from oxidative stress-induced apoptosis. Reason: Cardioprotection is a tissue-specific downstream effect of NRF2's antioxidant program. |
| GO:0010976 positive regulation of neuron projection development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NRF2 supports neuronal development through redox homeostasis. Reason: Neuronal development is a context-specific effect, not a core NRF2 function. |
| GO:0030194 positive regulation of blood coagulation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Inferred from mouse orthologs. Connection to coagulation is indirect. Reason: This is likely an indirect effect or based on limited evidence. Blood coagulation regulation is not a well-established NRF2 function. |
| GO:0032993 protein-DNA complex | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 forms protein-DNA complexes with small MAF proteins at AREs. Reason: NRF2:sMAF heterodimers bound to ARE DNA represent the active transcription complex. |
| GO:0034599 cellular response to oxidative stress | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate of IBA annotation for oxidative stress response. Reason: Core function of NRF2 confirmed by multiple evidence types. |
| GO:0034976 response to endoplasmic reticulum stress | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 is activated during ER stress as part of the unfolded protein response. Reason: ER stress activates NRF2 through PERK-mediated phosphorylation, connecting the antioxidant response to proteostasis. |
| GO:0036499 PERK-mediated unfolded protein response | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 is phosphorylated by PERK during UPR, promoting nuclear translocation. Reason: PERK phosphorylation of NRF2 is a key mechanism connecting ER stress to antioxidant defense. |
| GO:0042149 cellular response to glucose starvation | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 is activated during metabolic stress including glucose deprivation. Reason: Metabolic stress activates NRF2 to maintain redox homeostasis. |
| GO:0043536 positive regulation of blood vessel endothelial cell migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NRF2 promotes angiogenesis in part through endothelial cell migration. Reason: Angiogenesis promotion is a downstream effect of NRF2 in vascular biology contexts. |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 binds specifically to ARE consensus sequences (TGACnnnGC). Reason: Core molecular function of NRF2 as an ARE-binding transcription factor. |
| GO:0045088 regulation of innate immune response | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 modulates innate immunity by suppressing pro-inflammatory gene expression and regulating STING signaling. Reason: NRF2 plays an important role in inflammatory regulation by inhibiting NF-kB signaling and suppressing cytokine production. |
| GO:0045454 cell redox homeostasis | IEA GO_REF:0000120 | ACCEPT | Summary: NRF2 maintains cellular redox balance by inducing antioxidant genes. Reason: Core function of NRF2. Target genes include GCLC, GCLM, TXN, PRDX, NQO1. |
| GO:0045766 positive regulation of angiogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NRF2 promotes angiogenesis through VEGF pathway regulation. Reason: Pro-angiogenic effect is context-dependent, not a core NRF2 function. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000120 | ACCEPT | Summary: NRF2 activates Pol II-mediated transcription of target genes. Reason: Core function as a transcriptional activator. |
| GO:0046223 aflatoxin catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NRF2 induces enzymes that detoxify aflatoxin and other xenobiotics. Reason: Aflatoxin detoxification is a specific example of NRF2's broader xenobiotic detoxification function. |
| GO:0046326 positive regulation of D-glucose import across plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NRF2 regulates glucose transporter expression. Reason: Metabolic regulation is a downstream effect of NRF2, not a core function. |
| GO:0061431 cellular response to methionine | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NRF2 responds to methionine-related stress (possibly through homocysteine). Reason: Specific metabolic response, not a core NRF2 function. |
| GO:0071356 cellular response to tumor necrosis factor | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 mediates cellular responses to TNF through anti-inflammatory mechanisms. Reason: NRF2 cross-talks with inflammatory signaling pathways and can be activated by TNF-induced oxidative stress. |
| GO:0071456 cellular response to hypoxia | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 is activated by hypoxia and provides cytoprotection. Reason: Hypoxia activates NRF2 through ROS generation and HIF crosstalk. |
| GO:1900038 negative regulation of cellular response to hypoxia | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NRF2 can modulate hypoxic responses through HIF pathway crosstalk. Reason: Context-dependent regulatory effect, not a primary NRF2 function. |
| GO:1902037 negative regulation of hematopoietic stem cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NRF2 affects HSC differentiation through redox regulation. Reason: Hematopoietic effects are tissue-specific downstream consequences. |
| GO:1903788 positive regulation of glutathione biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 induces GCLC and GCLM, the rate-limiting enzymes for glutathione synthesis. Reason: Core function of NRF2. Glutathione synthesis genes are canonical NRF2 targets. |
| GO:1904385 cellular response to angiotensin | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Angiotensin II induces oxidative stress that activates NRF2. Reason: Cardiovascular-specific stimulus response, not a core NRF2 function. |
| GO:1904753 negative regulation of vascular associated smooth muscle cell migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NRF2 affects smooth muscle cell behavior in vascular contexts. Reason: Vascular biology-specific effect, not a core NRF2 function. |
| GO:2000121 regulation of removal of superoxide radicals | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 induces SOD and other enzymes that remove superoxide. Reason: Core function as part of the antioxidant response. |
| GO:2000379 positive regulation of reactive oxygen species metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: NRF2 regulates ROS metabolism through induction of antioxidant enzymes. Reason: Core function. NRF2 coordinates the cellular ROS detoxification machinery. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based localization from Human Protein Atlas showing nuclear NRF2. Reason: Nuclear localization is essential for NRF2 transcription factor function. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence showing cytosolic NRF2 (likely under basal conditions with KEAP1). Reason: Cytosolic localization reflects KEAP1-bound NRF2 under unstressed conditions. |
| GO:0005634 nucleus | NAS PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... | ACCEPT | Summary: bZIP protein interaction networks study noting NRF2 nuclear function. Reason: Consistent with multiple other annotations for nuclear localization. Supporting Evidence: PMID:23661758 Networks of bZIP protein-protein interactions diversified over a billion years of evolution. |
| GO:0006357 regulation of transcription by RNA polymerase II | NAS PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... | ACCEPT | Summary: bZIP transcription factor network study. Reason: Consistent with IBA and other annotations for this process. Supporting Evidence: PMID:23661758 Networks of bZIP protein-protein interactions diversified over a billion years of evolution. |
| GO:0140467 integrated stress response signaling | NAS PMID:28566324 Multi-omics analysis identifies ATF4 as a key regulator of t... | ACCEPT | Summary: ATF4-NRF2 complex participates in integrated stress response. Reason: NRF2 is a component of the integrated stress response, working with ATF4 to coordinate cytoprotective gene expression. Supporting Evidence: PMID:28566324 2017 May 31. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. |
| GO:0030217 T cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse ortholog data showing NRF2 role in T cell development. Reason: T cell effects are tissue-specific and not a primary NRF2 function. |
| GO:0006979 response to oxidative stress | IDA PMID:36075446 FOXO4 mediates resistance to oxidative stress in lens epithe... | ACCEPT | Summary: FOXO4 modulates NRF2 signaling in lens epithelial cells during oxidative stress. Reason: Core function of NRF2 as the master oxidative stress response transcription factor. Supporting Evidence: PMID:36075446 2022 Sep 6. FOXO4 mediates resistance to oxidative stress in lens epithelial cells by modulating the TRIM25/Nrf2 signaling. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, ... | ACCEPT | Summary: DJ-1 stabilizes NRF2, allowing it to bind cis-regulatory AREs. Reason: Core molecular function of NRF2. Supporting Evidence: PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, ... | ACCEPT | Summary: NRF2 activates Pol II transcription from ARE-containing promoters. Reason: Core molecular function demonstrated through DJ-1 stabilization experiments. Supporting Evidence: PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. |
| GO:0110076 negative regulation of ferroptosis | IMP PMID:26403645 Activation of the p62-Keap1-NRF2 pathway protects against fe... | ACCEPT | Summary: Landmark study demonstrating NRF2 protects hepatocellular carcinoma cells against ferroptosis through induction of NQO1, HMOX1, and FTH1. Reason: This is a core function of NRF2 in cancer and normal cells. NRF2 induces ferroptosis defense genes including glutathione synthesis (via GCLC/GCLM), iron storage (FTH1), and lipid peroxide detoxification enzymes. Supporting Evidence: PMID:26403645 Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. |
| GO:1904294 positive regulation of ERAD pathway | TAS PMID:23800989 Nrf2 and Nrf1 signaling and ER stress crosstalk: implication... | ACCEPT | Summary: NRF2 induces proteasome subunit genes and ER-associated degradation components. Reason: NRF2 coordinates proteostasis by inducing proteasome genes and ERAD components. Supporting Evidence: PMID:23800989 Epub 2013 Jun 26. Nrf2 and Nrf1 signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy. |
| GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process | TAS PMID:23800989 Nrf2 and Nrf1 signaling and ER stress crosstalk: implication... | ACCEPT | Summary: NRF2 promotes proteasome activity through induction of proteasome subunit genes. Reason: Connection to proteostasis through transcriptional activation of proteasome genes. Supporting Evidence: PMID:23800989 Epub 2013 Jun 26. Nrf2 and Nrf1 signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | ACCEPT | Summary: Laminar flow activates ERK5 leading to NRF2-mediated transcription in endothelium. Reason: Core function of NRF2 as a transcriptional activator. Supporting Evidence: PMID:23043106 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:24844779 Hypoxia-responsive microRNA-101 promotes angiogenesis via he... | ACCEPT | Summary: Hypoxia-responsive miR-101 promotes NRF2-mediated HO-1 induction. Reason: Core transcriptional activation function of NRF2. Supporting Evidence: PMID:24844779 Epub 2014 Jul 29. Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3. |
| GO:0071456 cellular response to hypoxia | IMP PMID:24844779 Hypoxia-responsive microRNA-101 promotes angiogenesis via he... | ACCEPT | Summary: NRF2 is activated during hypoxia and promotes cytoprotective gene expression. Reason: Hypoxia activates NRF2 through ROS and other mechanisms. Supporting Evidence: PMID:24844779 Epub 2014 Jul 29. Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IMP PMID:22492997 DJ-1 induces thioredoxin 1 expression through the Nrf2 pathw... | ACCEPT | Summary: DJ-1 induces thioredoxin 1 expression through NRF2 pathway. Reason: Core molecular function of NRF2. Supporting Evidence: PMID:22492997 Apr 5. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:22492997 DJ-1 induces thioredoxin 1 expression through the Nrf2 pathw... | ACCEPT | Summary: NRF2 activates TXN1 transcription through ARE binding. Reason: Core function demonstrated through TXN1 as a target gene. Supporting Evidence: PMID:22492997 Apr 5. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. |
| GO:0070301 cellular response to hydrogen peroxide | IGI PMID:22492997 DJ-1 induces thioredoxin 1 expression through the Nrf2 pathw... | ACCEPT | Summary: DJ-1 and NRF2 cooperate in H2O2 response through TXN1 induction. Reason: H2O2 is a key ROS that activates NRF2 through KEAP1 cysteine modification. Supporting Evidence: PMID:22492997 Apr 5. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. |
| GO:0034599 cellular response to oxidative stress | IDA PMID:36075446 FOXO4 mediates resistance to oxidative stress in lens epithe... | ACCEPT | Summary: FOXO4-NRF2 signaling in lens epithelial oxidative stress response. Reason: Core function of NRF2. Supporting Evidence: PMID:36075446 2022 Sep 6. FOXO4 mediates resistance to oxidative stress in lens epithelial cells by modulating the TRIM25/Nrf2 signaling. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9796067 | ACCEPT | Summary: PRKAA2 phosphorylates nuclear NRF2. Reason: Nuclear localization essential for NRF2 function. |
| GO:0016592 mediator complex | EXP PMID:32727915 Activation of NRF2 ameliorates oxidative stress and cystogen... | ACCEPT | Summary: NRF2 interacts with Mediator complex components for transcriptional activation. Reason: NRF2 recruits Mediator complex to enhance transcription of target genes. Supporting Evidence: PMID:32727915 Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease. |
| GO:0031625 ubiquitin protein ligase binding | IEP PMID:16888629 Structure of the Keap1:Nrf2 interface provides mechanistic i... | ACCEPT | Summary: NRF2 ETGE motif binds KEAP1 Kelch domain, targeting NRF2 for CUL3 E3 ligase complex. Reason: Core regulatory mechanism. The KEAP1-CUL3-RBX1 complex ubiquitinates NRF2. Supporting Evidence: PMID:16888629 Aug 3. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:24366543 Kinetic, thermodynamic, and structural characterizations of ... | ACCEPT | Summary: Detailed characterization of NRF2 DLGex degron binding to KEAP1. Reason: Characterizes the low-affinity DLG binding site for KEAP1. Supporting Evidence: PMID:24366543 Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1. |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:32727915 Activation of NRF2 ameliorates oxidative stress and cystogen... | ACCEPT | Summary: NRF2 activation ameliorates oxidative stress in polycystic kidney disease. Reason: Core function as a transcriptional activator. Supporting Evidence: PMID:32727915 Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease. |
| GO:0140693 molecular condensate scaffold activity | IDA PMID:32727915 Activation of NRF2 ameliorates oxidative stress and cystogen... | ACCEPT | Summary: NRF2 can form biomolecular condensates involved in transcriptional regulation. Reason: Novel aspect of NRF2 function in transcriptional regulation through phase separation. Supporting Evidence: PMID:32727915 Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease. |
| GO:1900407 regulation of cellular response to oxidative stress | EXP PMID:34299054 Nrf2, the Major Regulator of the Cellular Oxidative Stress R... | ACCEPT | Summary: Study on NRF2 intrinsic disorder and its role in oxidative stress regulation. Reason: Core function of NRF2 as the master regulator of oxidative stress response. Supporting Evidence: PMID:34299054 Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8932355 | ACCEPT | Summary: 26S proteasome degrades ubiquitinated NRF2 in cytosol. Reason: Cytosolic degradation of KEAP1-bound NRF2. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9755505 | ACCEPT | Summary: KEAP1:CUL3:RBX1 complex ubiquitinates NRF2 in cytosol. Reason: Cytosolic ubiquitination precedes degradation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9755507 | ACCEPT | Summary: VCP/p97 complex extracts ubiquitinated NRF2 for degradation. Reason: Cytosolic degradation pathway. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9758090 | ACCEPT | Summary: Ubiquitinated NRF2 extraction from CRL3 complex. Reason: Part of cytosolic degradation mechanism. |
| GO:0045088 regulation of innate immune response | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse ortholog showing NRF2 role in innate immunity. Reason: NRF2 regulates innate immunity by suppressing inflammatory cytokine production and modulating STING signaling. |
| GO:0005515 protein binding | IPI PMID:29983246 The Mitochondrial-Encoded Peptide MOTS-c Translocates to the... | ACCEPT | Summary: MOTS-c mitochondrial peptide translocates to nucleus and interacts with NRF2. Reason: Novel interaction connecting mitochondrial stress signaling to NRF2 activation. Supporting Evidence: PMID:29983246 2018 Jul 5. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9796047 | ACCEPT | Summary: PRKAA2-regulated nuclear export of NRF2. Reason: Nuclear localization for transcription factor activity. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9796047 | ACCEPT | Summary: NRF2 in cytosol for export regulation. Reason: Cytosolic localization for KEAP1-mediated regulation. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:20452972 p62/SQSTM1 is a target gene for transcription factor NRF2 an... | ACCEPT | Summary: Chromatin immunoprecipitation demonstrating NRF2 binding to ARE in p62 promoter. Reason: Core molecular function with direct experimental evidence. Supporting Evidence: PMID:20452972 2010 May 7. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:20452972 p62/SQSTM1 is a target gene for transcription factor NRF2 an... | ACCEPT | Summary: NRF2 demonstrated to function as ARE-binding transcription factor. Reason: Core molecular function. Supporting Evidence: PMID:20452972 2010 May 7. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. |
| GO:0005515 protein binding | IPI PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | MODIFY | Summary: NRF2 interacts with KEAP1 for ubiquitination targeting. Reason: The specific KEAP1 interaction should be annotated as ubiquitin protein ligase binding. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0005634 nucleus | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | ACCEPT | Summary: NRF2 detected in nucleus upon stabilization. Reason: Nuclear localization essential for transcription factor function. Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0005737 cytoplasm | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | ACCEPT | Summary: NRF2 accumulates in cytoplasm when proteasome is inhibited while KEAP1 is present. Reason: Cytoplasmic localization when sequestered by KEAP1. Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0034599 cellular response to oxidative stress | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse ortholog (NRF2/NFE2L2). Reason: Core function conserved across mammals. |
| GO:0043565 sequence-specific DNA binding | IDA PMID:20452972 p62/SQSTM1 is a target gene for transcription factor NRF2 an... | ACCEPT | Summary: Gel mobility shift assays showing NRF2 sequence-specific binding to ARE. Reason: Core molecular function demonstrated with direct binding assays. Supporting Evidence: PMID:20452972 2010 May 7. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: NRF2 as a sequence-specific DNA-binding transcription factor associates with chromatin. Reason: Appropriate for a DNA-binding transcription factor. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass annotation for NRF2 as a Pol II-specific transcription factor. Reason: Core molecular function. |
| GO:0045454 cell redox homeostasis | IMP PMID:29018201 Activating de novo mutations in NFE2L2 encoding NRF2 cause a... | ACCEPT | Summary: Activating NRF2 mutations cause altered cellular redox state in patients with IMDDHH. Reason: Core function demonstrated through human disease mutations. Supporting Evidence: PMID:29018201 Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder. |
| GO:0010628 positive regulation of gene expression | IMP PMID:27155659 Hepatitis B virus inhibits insulin receptor signaling and im... | ACCEPT | Summary: NRF2 regulates gene expression during liver regeneration. Reason: Core function as a transcriptional activator. Supporting Evidence: PMID:27155659 Epub 2016 May 7. Hepatitis B virus inhibits insulin receptor signaling and impairs liver regeneration via intracellular retention of the insulin receptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9796053 | ACCEPT | Summary: PKC phosphorylates NRF2 in cytosol. Reason: Cytosolic phosphorylation regulates NRF2 activity. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8932327 | ACCEPT | Summary: NRF2 binds KEAP1:NEDD8-CUL3:RBX1 in cytosol. Reason: Cytosolic KEAP1 complex interaction. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9712274 | ACCEPT | Summary: NRF2 inducers bind KEAP1:CUL3:RBX1:NRF2 in cytosol. Reason: Site of electrophile-mediated NRF2 stabilization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9762100 | ACCEPT | Summary: MYC and NICD1-dependent NFE2L2 gene expression. Reason: Cytosolic presence for regulation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9796046 | ACCEPT | Summary: NFkB-dependent NFE2L2 expression. Reason: Cytosolic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9796060 | ACCEPT | Summary: NFE2L2-dependent NFE2L2 expression (autoregulation). Reason: Cytosolic NRF2 population. |
| GO:0034599 cellular response to oxidative stress | TAS PMID:22934019 The endoplasmic reticulum stress response in aging and age-r... | ACCEPT | Summary: ER stress and aging review connecting NRF2 to oxidative stress response. Reason: Core function of NRF2. Supporting Evidence: PMID:22934019 The endoplasmic reticulum stress response in aging and age-related diseases. |
| GO:0036499 PERK-mediated unfolded protein response | TAS PMID:22934019 The endoplasmic reticulum stress response in aging and age-r... | ACCEPT | Summary: NRF2 is phosphorylated by PERK during UPR. Reason: PERK-NRF2 connection links ER stress to antioxidant defense. Supporting Evidence: PMID:22934019 The endoplasmic reticulum stress response in aging and age-related diseases. |
| GO:0036499 PERK-mediated unfolded protein response | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse ortholog showing PERK phosphorylation of NRF2. Reason: Conserved mechanism across mammals. |
| GO:0034599 cellular response to oxidative stress | NAS PMID:22013210 The unfolded protein response: integrating stress signals th... | ACCEPT | Summary: Review connecting UPR to oxidative stress through IRE1 and NRF2. Reason: Core function. Supporting Evidence: PMID:22013210 The unfolded protein response: integrating stress signals through the stress sensor IRE1Ξ±. |
| GO:0005515 protein binding | IPI PMID:21597468 Transformation of eEF1BΞ΄ into heat-shock response transcript... | ACCEPT | Summary: EEF1D alternative splicing creates heat shock transcription factor that interacts with NRF2. Reason: Shows NRF2 integration with heat shock response. Supporting Evidence: PMID:21597468 Transformation of eEF1BΞ΄ into heat-shock response transcription factor by alternative splicing. |
| GO:0030968 endoplasmic reticulum unfolded protein response | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse showing NRF2 role in UPR. Reason: NRF2 is activated during UPR to maintain redox homeostasis. |
| GO:0032993 protein-DNA complex | ISS GO_REF:0000024 | ACCEPT | Summary: NRF2:sMAF:ARE complex transferred from mouse. Reason: Core aspect of NRF2 function as ARE-binding transcription factor. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:25190803 Unspliced X-box-binding protein 1 (XBP1) protects endothelia... | ACCEPT | Summary: XBP1-NRF2 interaction protects endothelial cells. Reason: Core transcriptional activation function. Supporting Evidence: PMID:25190803 Epub 2014 Sep 4. Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3. |
| GO:0071498 cellular response to fluid shear stress | IDA PMID:25190803 Unspliced X-box-binding protein 1 (XBP1) protects endothelia... | ACCEPT | Summary: Shear stress activates NRF2 in endothelial cells. Reason: Mechanical stress can activate NRF2 through ROS generation. Supporting Evidence: PMID:25190803 Epub 2014 Sep 4. Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3. |
| GO:0005634 nucleus | IDA PMID:22492997 DJ-1 induces thioredoxin 1 expression through the Nrf2 pathw... | ACCEPT | Summary: Nuclear NRF2 detected after DJ-1-mediated stabilization. Reason: Nuclear localization for transcription. Supporting Evidence: PMID:22492997 Apr 5. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. |
| GO:0005737 cytoplasm | IDA PMID:22492997 DJ-1 induces thioredoxin 1 expression through the Nrf2 pathw... | ACCEPT | Summary: Cytoplasmic NRF2 detected in basal conditions. Reason: Cytoplasmic when KEAP1-bound. Supporting Evidence: PMID:22492997 Apr 5. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. |
| GO:0000976 transcription cis-regulatory region binding | TAS PMID:24252804 The role of oxidative stress in Parkinson's disease. | ACCEPT | Summary: Review on oxidative stress in Parkinson's disease noting NRF2 ARE binding. Reason: Core molecular function. Supporting Evidence: PMID:24252804 The role of oxidative stress in Parkinson's disease. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, ... | ACCEPT | Summary: DJ-1 stabilization of NRF2 promotes transcription of target genes. Reason: Core function. Supporting Evidence: PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. |
| GO:1902176 negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway | IMP PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | ACCEPT | Summary: ERK5-NRF2 pathway prevents oxidative stress-induced apoptosis in endothelium. Reason: Anti-apoptotic effect is a key consequence of NRF2 antioxidant function. Supporting Evidence: PMID:23043106 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. |
| GO:2000352 negative regulation of endothelial cell apoptotic process | IMP PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | KEEP AS NON CORE | Summary: NRF2 protects endothelial cells from apoptosis. Reason: Endothelial protection is a tissue-specific effect. Supporting Evidence: PMID:23043106 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. |
| GO:0005634 nucleus | IDA PMID:18202225 HO-1 underlies resistance of AML cells to TNF-induced apopto... | ACCEPT | Summary: Nuclear NRF2 in AML cells contributes to TNF resistance. Reason: Nuclear localization for transcription. Supporting Evidence: PMID:18202225 2008 Jan 17. HO-1 underlies resistance of AML cells to TNF-induced apoptosis. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:18202225 HO-1 underlies resistance of AML cells to TNF-induced apopto... | ACCEPT | Summary: NRF2 promotes HO-1 transcription in AML cells. Reason: Core function. Supporting Evidence: PMID:18202225 2008 Jan 17. HO-1 underlies resistance of AML cells to TNF-induced apoptosis. |
| GO:0071356 cellular response to tumor necrosis factor | IMP PMID:18202225 HO-1 underlies resistance of AML cells to TNF-induced apopto... | ACCEPT | Summary: NRF2 mediates resistance to TNF-induced apoptosis through HO-1. Reason: NRF2 is activated by TNF and provides cytoprotection. Supporting Evidence: PMID:18202225 2008 Jan 17. HO-1 underlies resistance of AML cells to TNF-induced apoptosis. |
| GO:0010499 proteasomal ubiquitin-independent protein catabolic process | IDA PMID:19424503 Ectodermal-neural cortex 1 down-regulates Nrf2 at the transl... | ACCEPT | Summary: ENC1 promotes NRF2 degradation through ubiquitin-independent pathway. Reason: Alternative NRF2 degradation mechanism. Supporting Evidence: PMID:19424503 Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level. |
| GO:0016567 protein ubiquitination | IDA PMID:15983046 Ubiquitination of Keap1, a BTB-Kelch substrate adaptor prote... | ACCEPT | Summary: NRF2 is subject to ubiquitination by KEAP1-CUL3 complex. Reason: Core regulatory mechanism. NRF2 is a ubiquitin substrate. Supporting Evidence: PMID:15983046 2005 Jun 27. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:15983046 Ubiquitination of Keap1, a BTB-Kelch substrate adaptor prote... | ACCEPT | Summary: Ubiquitinated NRF2 is degraded by the proteasome. Reason: Core regulatory mechanism for NRF2 turnover. Supporting Evidence: PMID:15983046 2005 Jun 27. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. |
| GO:0005634 nucleus | IDA PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | ACCEPT | Summary: Nuclear NRF2 detected after ERK5 activation. Reason: Nuclear localization. Supporting Evidence: PMID:23043106 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. |
| GO:0005829 cytosol | IDA PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | ACCEPT | Summary: Cytosolic NRF2 in endothelial cells. Reason: Cytosolic localization under basal conditions. Supporting Evidence: PMID:23043106 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | ACCEPT | Summary: NRF2 interacts with ERK5 transcription factor. Reason: Interaction with other transcription factors for coordinate gene regulation. Supporting Evidence: PMID:23043106 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. |
| GO:0070301 cellular response to hydrogen peroxide | IMP PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | ACCEPT | Summary: NRF2 protects endothelial cells from H2O2. Reason: H2O2 is a key ROS that activates NRF2. Supporting Evidence: PMID:23043106 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. |
| GO:0071499 cellular response to laminar fluid shear stress | IMP PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | ACCEPT | Summary: Laminar flow activates NRF2 in atheroprotection. Reason: Mechanical stress activates NRF2 in vascular endothelium. Supporting Evidence: PMID:23043106 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. |
| GO:0005634 nucleus | IDA PMID:18554677 Metallothionein-III protects against 6-hydroxydopamine-induc... | ACCEPT | Summary: Metallothionein-III induces nuclear NRF2 localization. Reason: Nuclear localization for transcription. Supporting Evidence: PMID:18554677 Metallothionein-III protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a PI3K and ERK/Nrf2-dependent manner. |
| GO:0003677 DNA binding | IDA PMID:18554677 Metallothionein-III protects against 6-hydroxydopamine-induc... | ACCEPT | Summary: NRF2 DNA binding demonstrated for HO-1 promoter. Reason: Core molecular function. Supporting Evidence: PMID:18554677 Metallothionein-III protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a PI3K and ERK/Nrf2-dependent manner. |
| GO:0019904 protein domain specific binding | IPI PMID:11256947 Characterization of the interaction between the transcriptio... | ACCEPT | Summary: NRF2 leucine zipper domain interacts with PMF1 coiled-coil domain. Reason: Domain-specific interaction for transcriptional regulation. Supporting Evidence: PMID:11256947 Characterization of the interaction between the transcription factors human polyamine modulated factor (PMF-1) and NF-E2-related factor 2 (Nrf-2) in the transcriptional regulation of the spermidine/spermine N1-acetyltransferase (SSAT) gene. |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:7937919 Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like bas... | ACCEPT | Summary: Original cloning paper identifying NRF2 as NF-E2-like transcriptional activator. Reason: Foundational evidence for NRF2 transcription factor function. Supporting Evidence: PMID:7937919 Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. |
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