NFE2L2

UniProt ID: Q16236
Organism: Homo sapiens
Review Status: COMPLETE
πŸ“ Provide Detailed Feedback

Gene Description

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.

Existing Annotations Review

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.
PMID:26403645
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.

Core Functions

NRF2 functions as the master transcription factor for the antioxidant response, binding to antioxidant response elements (AREs) in target gene promoters via its bZIP domain. Upon stabilization by oxidative stress or electrophile exposure, NRF2 translocates to the nucleus, heterodimerizes with small MAF proteins, and activates transcription of cytoprotective genes.

Molecular Function:
DNA-binding transcription factor activity, RNA polymerase II-specific
Supporting Evidence:

NRF2 contains a CNC-bZIP DNA-binding domain (residues 497-560) that enables sequence-specific recognition of AREs with the core sequence 5'-TGACnnnGC-3'. Structural studies demonstrate the basis for DNA recognition by NRF2-MAF heterodimers.

Molecular Function:
RNA polymerase II cis-regulatory region sequence-specific DNA binding
Supporting Evidence:

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000043
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000113
Gene Ontology annotation of human sequence-specific DNA binding transcription factors (DbTFs) based on the TFClass database
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
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.
  • Original cloning and characterization of NRF2 as a bZIP transcription factor
PMID:15601839
BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase.
  • KEAP1 binds CUL3 via BTB domain and NRF2 via Kelch domain
  • KEAP1-CUL3-ROC1 complex ubiquitinates NRF2 for proteasomal degradation
  • Knocking down KEAP1 or CUL3 results in NRF2 protein accumulation
PMID:16888629
Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling.
  • Crystal structure of KEAP1 Kelch domain bound to NRF2 ETGE peptide at 1.5 angstrom resolution
  • ETGE motif forms beta-turn structure fitting into KEAP1 binding pocket
PMID:20452972
p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription.
  • ARE mapped in p62 promoter responsible for NRF2-mediated induction
  • ChIP and EMSA confirm NRF2 binds ARE in vivo and in vitro
  • p62 competes with NRF2 for KEAP1 binding, creating positive feedback
PMID:26403645
Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells.
  • NRF2 protects HCC cells against ferroptosis
  • NRF2 induces NQO1, HMOX1, and FTH1 to prevent ferroptosis
  • NRF2 inhibition sensitizes tumors to ferroptosis-inducing agents
PMID:29018201
Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder.
  • Mutations in NRF2 ETGE/DLG motifs cause IMDDHH disease
  • Patients have constitutive NRF2 activation with increased G6PD and GSR activity
  • Demonstrates in vivo effects of chronic NRF2 hyperactivation
PMID:17015834
DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2.
PMID:18048326
Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha.
PMID:18692475
A protein domain-based interactome network for C. elegans early embryogenesis.
PMID:18757741
Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy.
PMID:19706542
Nitric oxide activation of Keap1/Nrf2 signaling in human colon carcinoma cells.
PMID:21988832
Toward an understanding of the protein interaction network of the human liver.
PMID:23661758
Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:25684205
CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP proteins to spatially restrict TIAM1-RAC1 signaling.
PMID:26700459
Involvement of Nrf2 in proteasome inhibition-mediated induction of ORP150 in thyroid cancer cells.
PMID:28777872
The short isoform of PML-RARΞ± activates the NRF2/HO-1 pathway through a direct interaction with NRF2.
PMID:29792731
APR3 modulates oxidative stress and mitochondrial function in ARPE-19 cells.
PMID:31169361
A Case Study on the Keap1 Interaction with Peptide Sequence Epitopes Selected by the Peptidomic mRNA Display.
PMID:31262713
FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 binding.
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:32911434
A functionally defined high-density NRF2 interactome reveals new conditional regulators of ARE transactivation.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34591642
A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.
PMID:35512704
Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
PMID:36442525
ARD1 stabilizes NRF2 through direct interaction and promotes colon cancer progression.
PMID:37187359
Geniposide ameliorates dextran sulfate sodium-induced ulcerative colitis via KEAP1-Nrf2 signaling pathway.
PMID:38891776
Pin1 Downregulation Is Involved in Excess Retinoic Acid-Induced Failure of Neural Tube Closure.
PMID:39009827
Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.
PMID:28566324
Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals.
PMID:36075446
FOXO4 mediates resistance to oxidative stress in lens epithelial cells by modulating the TRIM25/Nrf2 signaling.
PMID:23800989
Nrf2 and Nrf1 signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy.
PMID:23043106
Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation.
PMID:24844779
Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3.
PMID:22492997
DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway.
PMID:32727915
Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease.
PMID:24366543
Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1.
PMID:34299054
Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered.
PMID:29983246
The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.
PMID:27155659
Hepatitis B virus inhibits insulin receptor signaling and impairs liver regeneration via intracellular retention of the insulin receptor.
PMID:22934019
The endoplasmic reticulum stress response in aging and age-related diseases.
PMID:22013210
The unfolded protein response: integrating stress signals through the stress sensor IRE1Ξ±.
PMID:21597468
Transformation of eEF1BΞ΄ into heat-shock response transcription factor by alternative splicing.
PMID:25190803
Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3.
PMID:24252804
The role of oxidative stress in Parkinson's disease.
PMID:18202225
HO-1 underlies resistance of AML cells to TNF-induced apoptosis.
PMID:19424503
Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level.
PMID:15983046
Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway.
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.
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.
Reactome:R-HSA-9796067
PRKAA2 phosphorylates nuclear NRF2
Reactome:R-HSA-8932355
26S proteasome degrades ubiquitinated NRF2
Reactome:R-HSA-9755505
KEAP1:CUL3:RBX1 complex ubiquitinates NRF2
Reactome:R-HSA-9755507
VCP/p97 complex extracts ubiquitinated NRF2 for degradation
Reactome:R-HSA-9758090
Ubiquitinated NRF2 extraction from CRL3 complex
Reactome:R-HSA-9796047
PRKAA2-regulated nuclear export of NRF2
Reactome:R-HSA-9796053
PKC phosphorylates NRF2 in cytosol
Reactome:R-HSA-8932327
NRF2 binds KEAP1:NEDD8-CUL3:RBX1 in cytosol
Reactome:R-HSA-9712274
NRF2 inducers bind KEAP1:CUL3:RBX1:NRF2 in cytosol
Reactome:R-HSA-9762100
MYC and NICD1-dependent NFE2L2 gene expression
Reactome:R-HSA-9796046
NFkB-dependent NFE2L2 expression
Reactome:R-HSA-9796060
NFE2L2-dependent NFE2L2 expression (autoregulation)
file:human/NFE2L2/NFE2L2-deep-research-falcon.md
Deep research report on NFE2L2

Tags

ferroptosis

πŸ“š Additional Documentation

Deep Research Bioreason

(NFE2L2-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:46 AM

Organism: Homo sapiens

Sequence:

MMDLELPPPGLPSQQDMDLIDILWRQDIDLGVSREVFDFSQRRKEYELEKQKKLEKERQEQLQKEQEKAFFAQLQLDEETGEFLPIQPAQHIQSETSGSANYSQVAHIPKSDALYFDDCMQLLAQTFPFVDDNEVSSATFQSLVPDIPGHIESPVFIATNQAQSPETSVAQVAPVDLDGMQQDIEQVWEELLSIPELQCLNIENDKLVETTMVPSPEAKLTEVDNYHFYSSIPSMEKEVGNCSPHFLNAFEDSFSSILSTEDPNQLTVNSLNSDATVNTDFGDEFYSAFIAEPSISNSMPSPATLSHSLSELLNGPIDVSDLSLCKAFNQNHPESTAEFNDSDSGISLNTSPSVASPEHSVESSSYGDTLLGLSDSEVEELDSAPGSVKQNGPKTPVHSSGDMVQPLSPSQGQSTHVHDAQCENTPEKELPVSPGHRKTPFTKDKHSSRLEAHLTRDELRAKALHIPFPVEKIINLPVVDFNEMMSKEQFNEAQLALIRDIRRRGKNKVAAQNCRKRKLENIVELEQDLDHLKDEKEKLLKEKGENDKSLHLLKKQLSTLYLEVFSMLRDEDGKPYSPSEYSLQQTRDGNVFLVPKSKKPDVKKN

Thinking Trace

I begin by examining the InterPro architecture. The sequence is encompassed by IPR047167 (Nuclear Factor Erythroid-derived 2-like family, residues 12–604), marking it as a member of the CNC-bZIP/NFE2L transcription factor family. Near the C-terminus, IPR008917 (Transcription factor, Skn-1-like, DNA-binding domain superfamily, residues 454–521) specifies a Skn-1/Nrf-like DNA-recognition module. This region is overlapped and refined by a Maf-type basic leucine zipper system: IPR004826 (Basic leucine zipper domain, Maf-type, residues 469–559) and IPR004827 (Basic-leucine zipper domain, residues 495–560), both embedded within IPR046347 (Basic-leucine zipper domain superfamily, residues 506–558). The ordered layoutβ€”broad NFE/Nrf family coverage across the full length followed by a concentrated C-terminal Maf-type bZIPβ€”creates a classical CNC-bZIP transcription factor architecture. The basic region dictates sequence-specific DNA binding to palindromic or pseudo-palindromic motifs, while the leucine zipper enforces obligate dimerization. The Maf-type signature biases the complex toward heterodimer formation with small Maf proteins, producing high-affinity assemblies on antioxidant/MARE-like elements.

This domain architecture causes two core molecular functions. First, the basic region and Skn-1-like fold enforce sequence-specific DNA binding and transcriptional regulation, aligning with GO:0003700 (transcription factor activity, sequence-specific DNA binding). Second, the Maf-type bZIP necessitates cooperative dimerization, supporting GO:0046983 (protein dimerization activity). Together, these properties define a dimeric DNA-binding regulator that recruits or repels transcriptional machinery depending on promoter context.

From these molecular functions, I infer the biological process. CNC-bZIP factors control RNA polymerase II–dependent transcription programs that govern erythroid and hematopoietic differentiation, oxidative stress responses, and metabolic adaptation. The combination of Skn-1-like DNA-binding and Maf-type dimerization is classically used to modulate erythroid gene circuits and cytoprotective pathways. Thus, the most parsimonious process assignment is regulation of transcription by RNA polymerase II, which causally follows from a sequence-specific DNA-binding bZIP regulator. While the precise physiological niche can vary, hematopoietic and erythroid programs are strongly indicated by the family identity and dimerization logic.

The cellular component follows naturally from function and architecture. DNA-binding transcription factors operate where chromatin resides; the absence of transmembrane segments and the presence of nuclear localization signals typical of bZIP factors argue for a nuclear location. This matches a soluble nuclear regulator that shuttles on and off chromatin as needed.

Mechanistically, I hypothesize that the protein forms obligate heterodimers via its Maf-type bZIP, most likely pairing with small Maf proteins to stabilize high-affinity promoter occupancy. Once bound, it recruits co-regulatorsβ€”co-activators or co-repressorsβ€”to tune RNA polymerase II initiation and elongation at erythroid and stress-responsive loci. Likely interaction partners include small Maf family members (MAFK/MafG, MAFF/MafK, MAFFL/MafF) as dimerization partners; additional transcriptional co-regulators that bridge to the basal machinery; and chromatin remodelers that adjust nucleosome accessibility at target promoters. This ensemble yields a nuclear transcriptional switch that coordinates erythroid gene expression and broader stress-adaptive programs.

Functional Summary

A nuclear, dimeric transcription regulator that uses a C-terminal basic leucine zipper module to bind specific DNA elements and control RNA polymerase II–dependent transcription programs. Its Maf-type dimerization surface favors heterodimer formation that stabilizes promoter occupancy at regulatory elements governing erythroid and stress-adaptive gene networks. Operating in the nucleus, it assembles with partner bZIP factors and co-regulators to fine-tune chromatin-associated transcriptional outputs.

UniProt Summary

May be a transcription factor.

InterPro Domains

  • Nuclear Factor Erythroid-derived 2-like (IPR047167, family) β€” residues 12-604
  • Transcription factor, Skn-1-like, DNA-binding domain superfamily (IPR008917, homologous_superfamily) β€” residues 454-521
  • Basic leucine zipper domain, Maf-type (IPR004826, domain) β€” residues 469-559
  • Basic-leucine zipper domain (IPR004827, domain) β€” residues 495-560
  • Basic-leucine zipper domain superfamily (IPR046347, homologous_superfamily) β€” residues 506-558

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), transcription regulator activity (GO:0140110), heterocyclic compound binding (GO:1901363), transcription factor activity, sequence-specific DNA binding (GO:0003700), organic cyclic compound binding (GO:0097159), protein binding (GO:0005515), transcription factor binding (GO:0008134), nucleic acid binding (GO:0003676), protein domain specific binding (GO:0019904), DNA-binding transcription factor binding (GO:0140297), transcription regulatory region nucleic acid binding (GO:0001067), DNA binding (GO:0003677), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), double-stranded DNA binding (GO:0003690), sequence-specific DNA binding (GO:0043565), transcription cis-regulatory region binding (GO:0000976), sequence-specific double-stranded DNA binding (GO:1990837)

Biological Process: biological_process (GO:0008150), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), signaling (GO:0023052), biological regulation (GO:0065007), response to stimulus (GO:0050896), cellular process (GO:0009987), metabolic process (GO:0008152), homeostatic process (GO:0042592), negative regulation of biological process (GO:0048519), negative regulation of signaling (GO:0023057), response to chemical (GO:0042221), nitrogen compound metabolic process (GO:0006807), cellular homeostasis (GO:0019725), regulation of cellular process (GO:0050794), regulation of response to stimulus (GO:0048583), cellular response to stimulus (GO:0051716), regulation of signaling (GO:0023051), negative regulation of cellular process (GO:0048523), signal transduction (GO:0007165), response to abiotic stimulus (GO:0009628), positive regulation of response to stimulus (GO:0048584), regulation of metabolic process (GO:0019222), organic substance metabolic process (GO:0071704), catabolic process (GO:0009056), cellular metabolic process (GO:0044237), positive regulation of metabolic process (GO:0009893), response to stress (GO:0006950), negative regulation of response to stimulus (GO:0048585), cell communication (GO:0007154), primary metabolic process (GO:0044238), positive regulation of cellular process (GO:0048522), response to hypoxia (GO:0001666), negative regulation of signal transduction (GO:0009968), negative regulation of cell death (GO:0060548), response to fluid shear stress (GO:0034405), positive regulation of response to endoplasmic reticulum stress (GO:1905898), regulation of response to stress (GO:0080134), cellular catabolic process (GO:0044248), response to oxygen levels (GO:0070482), regulation of signal transduction (GO:0009966), regulation of macromolecule metabolic process (GO:0060255), ER-nucleus signaling pathway (GO:0006984), regulation of catabolic process (GO:0009894), response to inorganic substance (GO:0010035), endoplasmic reticulum unfolded protein response (GO:0030968), response to topologically incorrect protein (GO:0035966), regulation of nitrogen compound metabolic process (GO:0051171), organic substance catabolic process (GO:1901575), cellular macromolecule metabolic process (GO:0044260), positive regulation of nitrogen compound metabolic process (GO:0051173), negative regulation of cell communication (GO:0010648), organonitrogen compound metabolic process (GO:1901564), positive regulation of macromolecule metabolic process (GO:0010604), cell redox homeostasis (GO:0045454), response to oxidative stress (GO:0006979), protein metabolic process (GO:0019538), regulation of cellular response to stress (GO:0080135), response to oxygen-containing compound (GO:1901700), macromolecule metabolic process (GO:0043170), response to organic substance (GO:0010033), positive regulation of biosynthetic process (GO:0009891), negative regulation of response to oxidative stress (GO:1902883), regulation of cell death (GO:0010941), positive regulation of cellular metabolic process (GO:0031325), regulation of cell communication (GO:0010646), cellular response to chemical stimulus (GO:0070887), cellular response to stress (GO:0033554), regulation of biosynthetic process (GO:0009889), regulation of cellular metabolic process (GO:0031323), regulation of primary metabolic process (GO:0080090), positive regulation of catabolic process (GO:0009896), cellular response to oxidative stress (GO:0034599), regulation of macromolecule biosynthetic process (GO:0010556), cellular response to oxygen levels (GO:0071453), regulation of protein metabolic process (GO:0051246), negative regulation of programmed cell death (GO:0043069), regulation of programmed cell death (GO:0043067), protein catabolic process (GO:0030163), negative regulation of response to reactive oxygen species (GO:1901032), regulation of gene expression (GO:0010468), regulation of response to endoplasmic reticulum stress (GO:1905897), positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus (GO:1901522), regulation of cellular response to oxidative stress (GO:1900407), macromolecule catabolic process (GO:0009057), macromolecule modification (GO:0043412), regulation of oxidative stress-induced cell death (GO:1903201), response to decreased oxygen levels (GO:0036293), regulation of response to oxidative stress (GO:1902882), regulation of DNA-templated transcription in response to stress (GO:0043620), cellular response to fluid shear stress (GO:0071498), regulation of RNA metabolic process (GO:0051252), cellular response to oxygen-containing compound (GO:1901701), cellular response to hypoxia (GO:0071456), integrated stress response signaling (GO:0140467), response to cytokine (GO:0034097), organonitrogen compound catabolic process (GO:1901565), proteolysis (GO:0006508), regulation of protein catabolic process (GO:0042176), cellular response to organic substance (GO:0071310), cellular response to chemical stress (GO:0062197), positive regulation of gene expression (GO:0010628), negative regulation of apoptotic signaling pathway (GO:2001234), negative regulation of intracellular signal transduction (GO:1902532), regulation of apoptotic signaling pathway (GO:2001233), negative regulation of oxidative stress-induced cell death (GO:1903202), protein modification process (GO:0036211), response to laminar fluid shear stress (GO:0034616), response to endoplasmic reticulum stress (GO:0034976), positive regulation of macromolecule biosynthetic process (GO:0010557), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), positive regulation of RNA metabolic process (GO:0051254), cellular response to topologically incorrect protein (GO:0035967), cellular macromolecule catabolic process (GO:0044265), regulation of cellular biosynthetic process (GO:0031326), positive regulation of ERAD pathway (GO:1904294), positive regulation of protein metabolic process (GO:0051247), regulation of nucleobase-containing compound metabolic process (GO:0019219), positive regulation of protein catabolic process (GO:0045732), positive regulation of cellular catabolic process (GO:0031331), response to unfolded protein (GO:0006986), response to hydrogen peroxide (GO:0042542), regulation of cellular catabolic process (GO:0031329), response to reactive oxygen species (GO:0000302), positive regulation of cellular biosynthetic process (GO:0031328), regulation of intracellular signal transduction (GO:1902531), regulation of apoptotic process (GO:0042981), regulation of proteolysis (GO:0030162), regulation of RNA biosynthetic process (GO:2001141), cellular response to unfolded protein (GO:0034620), negative regulation of intrinsic apoptotic signaling pathway (GO:2001243), regulation of response to reactive oxygen species (GO:1901031), cellular response to cytokine stimulus (GO:0071345), positive regulation of RNA biosynthetic process (GO:1902680), regulation of transcription from RNA polymerase II promoter in response to stress (GO:0043618), cellular response to reactive oxygen species (GO:0034614), regulation of ubiquitin-dependent protein catabolic process (GO:2000058), regulation of hydrogen peroxide-induced cell death (GO:1903205), proteasomal protein catabolic process (GO:0010498), regulation of intrinsic apoptotic signaling pathway (GO:2001242), regulation of oxidative stress-induced intrinsic apoptotic signaling pathway (GO:1902175), negative regulation of apoptotic process (GO:0043066), protein modification by small protein conjugation or removal (GO:0070647), regulation of DNA-templated transcription (GO:0006355), modification-dependent macromolecule catabolic process (GO:0043632), proteolysis involved in protein catabolic process (GO:0051603), negative regulation of hydrogen peroxide-induced cell death (GO:1903206), cellular response to decreased oxygen levels (GO:0036294), regulation of ERAD pathway (GO:1904292), positive regulation of proteolysis (GO:0045862), positive regulation of proteasomal protein catabolic process (GO:1901800), response to tumor necrosis factor (GO:0034612), negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway (GO:1902176), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060), regulation of proteasomal protein catabolic process (GO:0061136), cellular response to hydrogen peroxide (GO:0070301), positive regulation of transcription from RNA polymerase II promoter in response to stress (GO:0036003), negative regulation of epithelial cell apoptotic process (GO:1904036), positive regulation of nucleic acid-templated transcription (GO:1903508), regulation of nucleic acid-templated transcription (GO:1903506), protein modification by small protein conjugation (GO:0032446), regulation of epithelial cell apoptotic process (GO:1904035), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), modification-dependent protein catabolic process (GO:0019941), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of proteolysis involved in protein catabolic process (GO:1903052), regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032434), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of proteolysis involved in protein catabolic process (GO:1903050), proteasomal ubiquitin-independent protein catabolic process (GO:0010499), cellular response to tumor necrosis factor (GO:0071356), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of endothelial cell apoptotic process (GO:2000351), ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), negative regulation of endothelial cell apoptotic process (GO:2000352)

Cellular Component: cellular_component (GO:0005575), protein-containing complex (GO:0032991), cellular anatomical entity (GO:0110165), microtubule organizing center (GO:0005815), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), membrane (GO:0016020), membrane-enclosed lumen (GO:0031974), cytosol (GO:0005829), nuclear protein-containing complex (GO:0140513), cytoplasm (GO:0005737), cell periphery (GO:0071944), transcription regulator complex (GO:0005667), endomembrane system (GO:0012505), nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794), RNA polymerase II transcription regulator complex (GO:0090575), organelle lumen (GO:0043233), centrosome (GO:0005813), intracellular organelle (GO:0043229), membrane-bounded organelle (GO:0043227), plasma membrane (GO:0005886), non-membrane-bounded organelle (GO:0043228), intracellular membrane-bounded organelle (GO:0043231), intracellular organelle lumen (GO:0070013), intracellular non-membrane-bounded organelle (GO:0043232), cytoskeleton (GO:0005856), nuclear lumen (GO:0031981), nucleus (GO:0005634), microtubule cytoskeleton (GO:0015630)

Generated by BioReason

Deep Research Bioreason Rl

(NFE2L2-deep-research-bioreason-rl.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:46 AM

Organism: Homo sapiens

Sequence:

MMDLELPPPGLPSQQDMDLIDILWRQDIDLGVSREVFDFSQRRKEYELEKQKKLEKERQEQLQKEQEKAFFAQLQLDEETGEFLPIQPAQHIQSETSGSANYSQVAHIPKSDALYFDDCMQLLAQTFPFVDDNEVSSATFQSLVPDIPGHIESPVFIATNQAQSPETSVAQVAPVDLDGMQQDIEQVWEELLSIPELQCLNIENDKLVETTMVPSPEAKLTEVDNYHFYSSIPSMEKEVGNCSPHFLNAFEDSFSSILSTEDPNQLTVNSLNSDATVNTDFGDEFYSAFIAEPSISNSMPSPATLSHSLSELLNGPIDVSDLSLCKAFNQNHPESTAEFNDSDSGISLNTSPSVASPEHSVESSSYGDTLLGLSDSEVEELDSAPGSVKQNGPKTPVHSSGDMVQPLSPSQGQSTHVHDAQCENTPEKELPVSPGHRKTPFTKDKHSSRLEAHLTRDELRAKALHIPFPVEKIINLPVVDFNEMMSKEQFNEAQLALIRDIRRRGKNKVAAQNCRKRKLENIVELEQDLDHLKDEKEKLLKEKGENDKSLHLLKKQLSTLYLEVFSMLRDEDGKPYSPSEYSLQQTRDGNVFLVPKSKKPDVKKN

Thinking Trace

I begin by examining the InterPro architecture. The sequence is encompassed by IPR047167 (Nuclear Factor Erythroid-derived 2-like family, residues 12–604), marking it as a member of the CNC-bZIP/NFE2L transcription factor family. Near the C-terminus, IPR008917 (Transcription factor, Skn-1-like, DNA-binding domain superfamily, residues 454–521) specifies a Skn-1/Nrf-like DNA-recognition module. This region is overlapped and refined by a Maf-type basic leucine zipper system: IPR004826 (Basic leucine zipper domain, Maf-type, residues 469–559) and IPR004827 (Basic-leucine zipper domain, residues 495–560), both embedded within IPR046347 (Basic-leucine zipper domain superfamily, residues 506–558). The ordered layoutβ€”broad NFE/Nrf family coverage across the full length followed by a concentrated C-terminal Maf-type bZIPβ€”creates a classical CNC-bZIP transcription factor architecture. The basic region dictates sequence-specific DNA binding to palindromic or pseudo-palindromic motifs, while the leucine zipper enforces obligate dimerization. The Maf-type signature biases the complex toward heterodimer formation with small Maf proteins, producing high-affinity assemblies on antioxidant/MARE-like elements.

This domain architecture causes two core molecular functions. First, the basic region and Skn-1-like fold enforce sequence-specific DNA binding and transcriptional regulation, aligning with GO:0003700 (transcription factor activity, sequence-specific DNA binding). Second, the Maf-type bZIP necessitates cooperative dimerization, supporting GO:0046983 (protein dimerization activity). Together, these properties define a dimeric DNA-binding regulator that recruits or repels transcriptional machinery depending on promoter context.

From these molecular functions, I infer the biological process. CNC-bZIP factors control RNA polymerase II–dependent transcription programs that govern erythroid and hematopoietic differentiation, oxidative stress responses, and metabolic adaptation. The combination of Skn-1-like DNA-binding and Maf-type dimerization is classically used to modulate erythroid gene circuits and cytoprotective pathways. Thus, the most parsimonious process assignment is regulation of transcription by RNA polymerase II, which causally follows from a sequence-specific DNA-binding bZIP regulator. While the precise physiological niche can vary, hematopoietic and erythroid programs are strongly indicated by the family identity and dimerization logic.

The cellular component follows naturally from function and architecture. DNA-binding transcription factors operate where chromatin resides; the absence of transmembrane segments and the presence of nuclear localization signals typical of bZIP factors argue for a nuclear location. This matches a soluble nuclear regulator that shuttles on and off chromatin as needed.

Mechanistically, I hypothesize that the protein forms obligate heterodimers via its Maf-type bZIP, most likely pairing with small Maf proteins to stabilize high-affinity promoter occupancy. Once bound, it recruits co-regulatorsβ€”co-activators or co-repressorsβ€”to tune RNA polymerase II initiation and elongation at erythroid and stress-responsive loci. Likely interaction partners include small Maf family members (MAFK/MafG, MAFF/MafK, MAFFL/MafF) as dimerization partners; additional transcriptional co-regulators that bridge to the basal machinery; and chromatin remodelers that adjust nucleosome accessibility at target promoters. This ensemble yields a nuclear transcriptional switch that coordinates erythroid gene expression and broader stress-adaptive programs.

Functional Summary

A nuclear, dimeric transcription regulator that uses a C-terminal basic leucine zipper module to bind specific DNA elements and control RNA polymerase II–dependent transcription programs. Its Maf-type dimerization surface favors heterodimer formation that stabilizes promoter occupancy at regulatory elements governing erythroid and stress-adaptive gene networks. Operating in the nucleus, it assembles with partner bZIP factors and co-regulators to fine-tune chromatin-associated transcriptional outputs.

UniProt Summary

May be a transcription factor.

InterPro Domains

  • Nuclear Factor Erythroid-derived 2-like (IPR047167, family) β€” residues 12-604
  • Transcription factor, Skn-1-like, DNA-binding domain superfamily (IPR008917, homologous_superfamily) β€” residues 454-521
  • Basic leucine zipper domain, Maf-type (IPR004826, domain) β€” residues 469-559
  • Basic-leucine zipper domain (IPR004827, domain) β€” residues 495-560
  • Basic-leucine zipper domain superfamily (IPR046347, homologous_superfamily) β€” residues 506-558

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), transcription regulator activity (GO:0140110), heterocyclic compound binding (GO:1901363), transcription factor activity, sequence-specific DNA binding (GO:0003700), organic cyclic compound binding (GO:0097159), protein binding (GO:0005515), transcription factor binding (GO:0008134), nucleic acid binding (GO:0003676), protein domain specific binding (GO:0019904), DNA-binding transcription factor binding (GO:0140297), transcription regulatory region nucleic acid binding (GO:0001067), DNA binding (GO:0003677), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), double-stranded DNA binding (GO:0003690), sequence-specific DNA binding (GO:0043565), transcription cis-regulatory region binding (GO:0000976), sequence-specific double-stranded DNA binding (GO:1990837)

Biological Process: biological_process (GO:0008150), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), signaling (GO:0023052), biological regulation (GO:0065007), response to stimulus (GO:0050896), cellular process (GO:0009987), metabolic process (GO:0008152), homeostatic process (GO:0042592), negative regulation of biological process (GO:0048519), negative regulation of signaling (GO:0023057), response to chemical (GO:0042221), nitrogen compound metabolic process (GO:0006807), cellular homeostasis (GO:0019725), regulation of cellular process (GO:0050794), regulation of response to stimulus (GO:0048583), cellular response to stimulus (GO:0051716), regulation of signaling (GO:0023051), negative regulation of cellular process (GO:0048523), signal transduction (GO:0007165), response to abiotic stimulus (GO:0009628), positive regulation of response to stimulus (GO:0048584), regulation of metabolic process (GO:0019222), organic substance metabolic process (GO:0071704), catabolic process (GO:0009056), cellular metabolic process (GO:0044237), positive regulation of metabolic process (GO:0009893), response to stress (GO:0006950), negative regulation of response to stimulus (GO:0048585), cell communication (GO:0007154), primary metabolic process (GO:0044238), positive regulation of cellular process (GO:0048522), response to hypoxia (GO:0001666), negative regulation of signal transduction (GO:0009968), negative regulation of cell death (GO:0060548), response to fluid shear stress (GO:0034405), positive regulation of response to endoplasmic reticulum stress (GO:1905898), regulation of response to stress (GO:0080134), cellular catabolic process (GO:0044248), response to oxygen levels (GO:0070482), regulation of signal transduction (GO:0009966), regulation of macromolecule metabolic process (GO:0060255), ER-nucleus signaling pathway (GO:0006984), regulation of catabolic process (GO:0009894), response to inorganic substance (GO:0010035), endoplasmic reticulum unfolded protein response (GO:0030968), response to topologically incorrect protein (GO:0035966), regulation of nitrogen compound metabolic process (GO:0051171), organic substance catabolic process (GO:1901575), cellular macromolecule metabolic process (GO:0044260), positive regulation of nitrogen compound metabolic process (GO:0051173), negative regulation of cell communication (GO:0010648), organonitrogen compound metabolic process (GO:1901564), positive regulation of macromolecule metabolic process (GO:0010604), cell redox homeostasis (GO:0045454), response to oxidative stress (GO:0006979), protein metabolic process (GO:0019538), regulation of cellular response to stress (GO:0080135), response to oxygen-containing compound (GO:1901700), macromolecule metabolic process (GO:0043170), response to organic substance (GO:0010033), positive regulation of biosynthetic process (GO:0009891), negative regulation of response to oxidative stress (GO:1902883), regulation of cell death (GO:0010941), positive regulation of cellular metabolic process (GO:0031325), regulation of cell communication (GO:0010646), cellular response to chemical stimulus (GO:0070887), cellular response to stress (GO:0033554), regulation of biosynthetic process (GO:0009889), regulation of cellular metabolic process (GO:0031323), regulation of primary metabolic process (GO:0080090), positive regulation of catabolic process (GO:0009896), cellular response to oxidative stress (GO:0034599), regulation of macromolecule biosynthetic process (GO:0010556), cellular response to oxygen levels (GO:0071453), regulation of protein metabolic process (GO:0051246), negative regulation of programmed cell death (GO:0043069), regulation of programmed cell death (GO:0043067), protein catabolic process (GO:0030163), negative regulation of response to reactive oxygen species (GO:1901032), regulation of gene expression (GO:0010468), regulation of response to endoplasmic reticulum stress (GO:1905897), positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus (GO:1901522), regulation of cellular response to oxidative stress (GO:1900407), macromolecule catabolic process (GO:0009057), macromolecule modification (GO:0043412), regulation of oxidative stress-induced cell death (GO:1903201), response to decreased oxygen levels (GO:0036293), regulation of response to oxidative stress (GO:1902882), regulation of DNA-templated transcription in response to stress (GO:0043620), cellular response to fluid shear stress (GO:0071498), regulation of RNA metabolic process (GO:0051252), cellular response to oxygen-containing compound (GO:1901701), cellular response to hypoxia (GO:0071456), integrated stress response signaling (GO:0140467), response to cytokine (GO:0034097), organonitrogen compound catabolic process (GO:1901565), proteolysis (GO:0006508), regulation of protein catabolic process (GO:0042176), cellular response to organic substance (GO:0071310), cellular response to chemical stress (GO:0062197), positive regulation of gene expression (GO:0010628), negative regulation of apoptotic signaling pathway (GO:2001234), negative regulation of intracellular signal transduction (GO:1902532), regulation of apoptotic signaling pathway (GO:2001233), negative regulation of oxidative stress-induced cell death (GO:1903202), protein modification process (GO:0036211), response to laminar fluid shear stress (GO:0034616), response to endoplasmic reticulum stress (GO:0034976), positive regulation of macromolecule biosynthetic process (GO:0010557), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), positive regulation of RNA metabolic process (GO:0051254), cellular response to topologically incorrect protein (GO:0035967), cellular macromolecule catabolic process (GO:0044265), regulation of cellular biosynthetic process (GO:0031326), positive regulation of ERAD pathway (GO:1904294), positive regulation of protein metabolic process (GO:0051247), regulation of nucleobase-containing compound metabolic process (GO:0019219), positive regulation of protein catabolic process (GO:0045732), positive regulation of cellular catabolic process (GO:0031331), response to unfolded protein (GO:0006986), response to hydrogen peroxide (GO:0042542), regulation of cellular catabolic process (GO:0031329), response to reactive oxygen species (GO:0000302), positive regulation of cellular biosynthetic process (GO:0031328), regulation of intracellular signal transduction (GO:1902531), regulation of apoptotic process (GO:0042981), regulation of proteolysis (GO:0030162), regulation of RNA biosynthetic process (GO:2001141), cellular response to unfolded protein (GO:0034620), negative regulation of intrinsic apoptotic signaling pathway (GO:2001243), regulation of response to reactive oxygen species (GO:1901031), cellular response to cytokine stimulus (GO:0071345), positive regulation of RNA biosynthetic process (GO:1902680), regulation of transcription from RNA polymerase II promoter in response to stress (GO:0043618), cellular response to reactive oxygen species (GO:0034614), regulation of ubiquitin-dependent protein catabolic process (GO:2000058), regulation of hydrogen peroxide-induced cell death (GO:1903205), proteasomal protein catabolic process (GO:0010498), regulation of intrinsic apoptotic signaling pathway (GO:2001242), regulation of oxidative stress-induced intrinsic apoptotic signaling pathway (GO:1902175), negative regulation of apoptotic process (GO:0043066), protein modification by small protein conjugation or removal (GO:0070647), regulation of DNA-templated transcription (GO:0006355), modification-dependent macromolecule catabolic process (GO:0043632), proteolysis involved in protein catabolic process (GO:0051603), negative regulation of hydrogen peroxide-induced cell death (GO:1903206), cellular response to decreased oxygen levels (GO:0036294), regulation of ERAD pathway (GO:1904292), positive regulation of proteolysis (GO:0045862), positive regulation of proteasomal protein catabolic process (GO:1901800), response to tumor necrosis factor (GO:0034612), negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway (GO:1902176), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060), regulation of proteasomal protein catabolic process (GO:0061136), cellular response to hydrogen peroxide (GO:0070301), positive regulation of transcription from RNA polymerase II promoter in response to stress (GO:0036003), negative regulation of epithelial cell apoptotic process (GO:1904036), positive regulation of nucleic acid-templated transcription (GO:1903508), regulation of nucleic acid-templated transcription (GO:1903506), protein modification by small protein conjugation (GO:0032446), regulation of epithelial cell apoptotic process (GO:1904035), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), modification-dependent protein catabolic process (GO:0019941), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of proteolysis involved in protein catabolic process (GO:1903052), regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032434), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of proteolysis involved in protein catabolic process (GO:1903050), proteasomal ubiquitin-independent protein catabolic process (GO:0010499), cellular response to tumor necrosis factor (GO:0071356), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of endothelial cell apoptotic process (GO:2000351), ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), negative regulation of endothelial cell apoptotic process (GO:2000352)

Cellular Component: cellular_component (GO:0005575), protein-containing complex (GO:0032991), cellular anatomical entity (GO:0110165), microtubule organizing center (GO:0005815), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), membrane (GO:0016020), membrane-enclosed lumen (GO:0031974), cytosol (GO:0005829), nuclear protein-containing complex (GO:0140513), cytoplasm (GO:0005737), cell periphery (GO:0071944), transcription regulator complex (GO:0005667), endomembrane system (GO:0012505), nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794), RNA polymerase II transcription regulator complex (GO:0090575), organelle lumen (GO:0043233), centrosome (GO:0005813), intracellular organelle (GO:0043229), membrane-bounded organelle (GO:0043227), plasma membrane (GO:0005886), non-membrane-bounded organelle (GO:0043228), intracellular membrane-bounded organelle (GO:0043231), intracellular organelle lumen (GO:0070013), intracellular non-membrane-bounded organelle (GO:0043232), cytoskeleton (GO:0005856), nuclear lumen (GO:0031981), nucleus (GO:0005634), microtubule cytoskeleton (GO:0015630)

Generated by BioReason

Deep Research Falcon

(NFE2L2-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2025-12-28T12:19:32.498910'
end_time: '2025-12-28T12:23:51.765722'
duration_seconds: 259.27
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: NFE2L2
gene_symbol: NFE2L2
uniprot_accession: Q16236
protein_description: 'RecName: Full=Nuclear factor erythroid 2-related factor 2
{ECO:0000303|PubMed:11035812}; Short=NF-E2-related factor 2 {ECO:0000303|PubMed:11035812};
Short=NFE2-related factor 2 {ECO:0000303|PubMed:11035812}; Short=Nrf-2 {ECO:0000303|PubMed:11256947};
AltName: Full=Nuclear factor, erythroid derived 2, like 2 {ECO:0000303|PubMed:33009401,
ECO:0000303|PubMed:7937919};'
gene_info: Name=NFE2L2 {ECO:0000303|PubMed:29018201, ECO:0000312|HGNC:HGNC:7782};
Synonyms=NRF2 {ECO:0000303|PubMed:33009401, ECO:0000303|PubMed:7937919};
organism_full: Homo sapiens (Human).
protein_family: Belongs to the bZIP family. CNC subfamily. .
protein_domains: bZIP. (IPR004827); bZIP_Maf. (IPR004826); bZIP_sf. (IPR046347);
NFE2-like. (IPR047167); TF_DNA-bd_sf. (IPR008917)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
citation_count: 11

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

  • UniProt Accession: Q16236
  • Protein Description: RecName: Full=Nuclear factor erythroid 2-related factor 2 {ECO:0000303|PubMed:11035812}; Short=NF-E2-related factor 2 {ECO:0000303|PubMed:11035812}; Short=NFE2-related factor 2 {ECO:0000303|PubMed:11035812}; Short=Nrf-2 {ECO:0000303|PubMed:11256947}; AltName: Full=Nuclear factor, erythroid derived 2, like 2 {ECO:0000303|PubMed:33009401, ECO:0000303|PubMed:7937919};
  • Gene Information: Name=NFE2L2 {ECO:0000303|PubMed:29018201, ECO:0000312|HGNC:HGNC:7782}; Synonyms=NRF2 {ECO:0000303|PubMed:33009401, ECO:0000303|PubMed:7937919};
  • Organism (full): Homo sapiens (Human).
  • Protein Family: Belongs to the bZIP family. CNC subfamily. .
  • Key Domains: bZIP. (IPR004827); bZIP_Maf. (IPR004826); bZIP_sf. (IPR046347); NFE2-like. (IPR047167); TF_DNA-bd_sf. (IPR008917)

MANDATORY VERIFICATION STEPS:

  1. Check if the gene symbol "NFE2L2" matches the protein description above
  2. Verify the organism is correct: Homo sapiens (Human).
  3. Check if protein family/domains align with what you find in literature
  4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'NFE2L2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene NFE2L2 (gene ID: NFE2L2, UniProt: Q16236) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

  • UniProt Accession: Q16236
  • Protein Description: RecName: Full=Nuclear factor erythroid 2-related factor 2 {ECO:0000303|PubMed:11035812}; Short=NF-E2-related factor 2 {ECO:0000303|PubMed:11035812}; Short=NFE2-related factor 2 {ECO:0000303|PubMed:11035812}; Short=Nrf-2 {ECO:0000303|PubMed:11256947}; AltName: Full=Nuclear factor, erythroid derived 2, like 2 {ECO:0000303|PubMed:33009401, ECO:0000303|PubMed:7937919};
  • Gene Information: Name=NFE2L2 {ECO:0000303|PubMed:29018201, ECO:0000312|HGNC:HGNC:7782}; Synonyms=NRF2 {ECO:0000303|PubMed:33009401, ECO:0000303|PubMed:7937919};
  • Organism (full): Homo sapiens (Human).
  • Protein Family: Belongs to the bZIP family. CNC subfamily. .
  • Key Domains: bZIP. (IPR004827); bZIP_Maf. (IPR004826); bZIP_sf. (IPR046347); NFE2-like. (IPR047167); TF_DNA-bd_sf. (IPR008917)

MANDATORY VERIFICATION STEPS:

  1. Check if the gene symbol "NFE2L2" matches the protein description above
  2. Verify the organism is correct: Homo sapiens (Human).
  3. Check if protein family/domains align with what you find in literature
  4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'NFE2L2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene NFE2L2 (gene ID: NFE2L2, UniProt: Q16236) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan overview
Objective 1 (verify identity) is complete: NFE2L2 encodes human NRF2 (UniProt Q16236), a Cap β€˜n’ Collar (CNC) basic leucine zipper (bZIP) transcription factor with hallmark Neh domains and KEAP1-binding motifs, consistent with the user-provided UniProt description (chen2024keap1nrf2pathwaya pages 4-5, shakya2024targetingnrf2driven pages 22-27). Objectives 2–5 (evidence gathering and synthesis) are completed with curated, recent sources. Objective 6 (final report) is fulfilled below.

Identity: NFE2L2 (NRF2), UniProt Q16236; organism: Homo sapiens; CNC‑bZIP family; key domains Neh1–Neh7 (Neh2 contains ETGE/DLG; Neh1 = CNC‑bZIP DNA‑binding/leucine zipper; Neh6 harbors β‑TrCP degrons) (chen2024keap1nrf2pathwaya pages 4-5, shakya2024targetingnrf2driven pages 22-27).

Canonical mechanism: KEAP1–CUL3–RBX1 adaptor E3 ligase mediates cytoplasmic ubiquitin‑dependent NRF2 degradation; KEAP1 cysteine sensors detect electrophiles/ROS, inhibiting NRF2 ubiquitylation and allowing newly synthesized NRF2 to translocate to the nucleus, heterodimerize with small MAFs, bind AREs and activate target genes (ex.: NQO1, HMOX1/HO‑1, GCLC/GCLM, SLC7A11) (shakya2024targetingnrf2driven pages 22-27, hasan2025moleculartargetsof pages 2-4, sparaneo2025decodingthenrf2–notch pages 2-4).

Subcellular localization: predominantly cytoplasmic when bound to KEAP1 under basal conditions; stress/electrophile exposure stabilizes NRF2 and drives nuclear accumulation and transcriptional activity (sparaneo2025decodingthenrf2–notch pages 4-5, sparaneo2025decodingthenrf2–notch pages 2-4).

Clinical relevance: recurrent activating NFE2L2 mutations cluster in exon 2 (disrupting DLG/ETGE motifs), with high prevalence in squamous lung cancers (LUSC/LUAD subsets) and context‑dependent effects on prognosis and immunotherapy outcomes (altered anti‑PD1 responses reported); therapeutic modulation includes approved NRF2 activators (e.g., dimethyl fumarate, omaveloxolone) and mixed clinical results for agents like bardoxolone (oskomic2025keap1nrf2interactionin pages 2-4, sparaneo2025decodingthenrf2–notch pages 4-5, panda2025nrf2immunobiologyin pages 1-2).

Blockquote: A concise, citable summary of human NFE2L2/NRF2 identity, domains, canonical mechanism, localization, and clinical relevance with supporting citations for rapid reference.

Comprehensive research report: NFE2L2 (NRF2) β€” human (UniProt Q16236)

1) Key concepts and definitions (current understanding)
- Identity and family: NRF2 (gene symbol NFE2L2) is a human CNC-bZIP transcription factor that heterodimerizes with small MAF proteins to bind antioxidant response elements (AREs) and regulate cytoprotective gene expression (sparaneo2025decodingthenrf2–notch pages 2-4). Neh1 contains the CNC-bZIP DNA-binding/leucine-zipper region; Neh2 harbors two KEAP1-binding degrons, DLG and ETGE; Neh6 encodes Ξ²-TrCP-responsive phosphodegrons; additional Neh3/4/5 transactivation and Neh7 RXRΞ±-repressor interfaces complete the regulatory topology (chen2024keap1nrf2pathwaya pages 4-5, shakya2024targetingnrf2driven pages 18-22).
- Canonical regulation: Under homeostasis, cytosolic KEAP1 (an obligate homodimer and CUL3–RBX1 E3 ligase adaptor) binds NRF2 via ETGE (high-affinity β€œhinge”) and DLG (low-affinity β€œlatch”) motifs and targets lysines in Neh2 for polyubiquitination and rapid proteasomal turnover (half-life ~15 min), keeping NRF2 levels low (panda2025nrf2immunobiologyin pages 1-2). Electrophiles/ROS modify reactive KEAP1 cysteines, suppressing NRF2 ubiquitination; newly synthesized NRF2 accumulates, translocates to the nucleus, dimerizes with small MAFs, and binds AREs to induce target genes (shakya2024targetingnrf2driven pages 22-27, hasan2025moleculartargetsof pages 2-4, sparaneo2025decodingthenrf2–notch pages 2-4). KEAP1-independent control includes GSK3β†’Ξ²-TrCP/CUL1-mediated degradation via Neh6 and autophagy-driven p62/SQSTM1 sequestration of KEAP1, among other post-translational and epigenetic inputs (hasan2025moleculartargetsof pages 2-4, sparaneo2025decodingthenrf2–notch pages 2-4).
- Subcellular localization: NRF2 is predominantly cytoplasmic when tethered to KEAP1 and accumulates in the nucleus upon stress or electrophile exposure to execute transcriptional programs (sparaneo2025decodingthenrf2–notch pages 4-5, sparaneo2025decodingthenrf2–notch pages 2-4).
- Core transcriptional program: NRF2 induces phase II detoxification and antioxidant genes including NQO1, HMOX1 (HO-1), GCLC/GCLM (glutathione synthesis), and SLC7A11 (cystine/glutamate antiporter), among >200 ARE-bearing targets; it impacts glutathione/NADPH metabolism, redox buffering, xenobiotic detoxification, and proteostasis (shakya2024targetingnrf2driven pages 22-27, hasan2025moleculartargetsof pages 2-4, sparaneo2025decodingthenrf2–notch pages 2-4).

2) Recent developments and latest research (2023–2024 priority)
- Structural/functional updates in regulation: Recent reviews synthesize domain-resolved behavior: Neh2/Neh7 segments display intrinsic disorder favoring dynamic recognition by KEAP1 and repressors, while Neh4/5 present structured transactivation interfaces (2024) (shakya2024targetingnrf2driven pages 18-22). Mechanistic refinements emphasize the 2:2:1 CUL3:KEAP1:NRF2 stoichiometry and multi-cysteine sensing by KEAP1 that toggles NRF2 stability (Oncogene, 2025; mechanistic framing remains current) (panda2025nrf2immunobiologyin pages 1-2). KEAP1 cysteine-centered electrophile sensing and p97-facilitated extraction of ubiquitylated NRF2 from the complex continue to be cited as core features (shakya2024targetingnrf2driven pages 22-27, hasan2025moleculartargetsof pages 2-4).
- Crosstalk with other pathways: Updated analyses highlight bidirectional interactions of NRF2 with NOTCH signaling in lung cancer, influencing metabolic reprogramming and tumor microenvironment (2025 update; mechanistic themes are continuous with prior literature) (sparaneo2025decodingthenrf2–notch pages 4-5, sparaneo2025decodingthenrf2–notch pages 2-4). Reviews in 2024–2025 also synthesize KEAP1-independent control via Ξ²-TrCP and autophagy (p62) and transcriptional control by inflammatory regulators (hasan2025moleculartargetsof pages 2-4, sparaneo2025decodingthenrf2–notch pages 2-4).
- Immuno-oncology insights: NRF2 hyperactivation associates with immune evasion and attenuated anti-PD-1 responses across several tumor types; emerging work dissects how NRF2 remodeling of metabolism and stress defenses suppresses cytotoxic immune activity (Oncogene, 2025) (panda2025nrf2immunobiologyin pages 1-2).

3) Current applications and real-world implementations
- Approved NRF2 activators: Dimethyl fumarate (DMF; Tecfidera) is an approved electrophilic NRF2 activator in multiple sclerosis; omaveloxolone is approved for Friedreich’s ataxia, reflecting clinical utility of NRF2 induction in neuroinflammatory/neurodegenerative contexts (oskomic2025keap1nrf2interactionin pages 2-4). These approvals operationalize the KEAP1-cysteine sensing mechanism to engage NRF2.
- Mixed outcomes in CKD: Bardoxolone methyl (CDDO-Me), a potent NRF2 activator, produced increases in eGFR but raised safety concerns (e.g., fluid retention, blood pressure), leading to mixed or negative outcomes in some kidney disease settings; contemporary reviews emphasize the need for disease- and stage-tailored modulation (summarized mechanistically and contextually) (oskomic2025keap1nrf2interactionin pages 2-4).
- Nutritional/electrophile approaches: Human dietary electrophiles (e.g., isothiocyanates such as sulforaphane) and other thiol-reactive small molecules activate NRF2 via KEAP1 cysteine modification; these strategies are being explored in prevention/adjunct settings and clinical trials (mechanism consolidated across KEAP1–NRF2 reviews) (shakya2024targetingnrf2driven pages 22-27, sparaneo2025decodingthenrf2–notch pages 2-4).

4) Expert opinions and analysis
- Dual-role paradigm: Authorities emphasize NRF2’s protective role in normal cells versus its proto-oncogenic potential when chronically hyperactivated, where it enhances proliferation, anabolic metabolism, and therapy resistanceβ€”particularly in tumors with KEAP1/NFE2L2 pathway alterations (sparaneo2025decodingthenrf2–notch pages 2-4, panda2025nrf2immunobiologyin pages 1-2). The Oncogene 2025 perspective underscores lack of approved NRF2 inhibitors and advocates context-specific strategies, including combination therapies to counter tumor dependencies created by NRF2 activation (panda2025nrf2immunobiologyin pages 1-2).
- Regulatory complexity: Recent syntheses detail multi-layered controlβ€”KEAP1 cysteine code, CUL3 neddylation, Ξ²-TrCP/GSK3 axis, p62/autophagy, microRNA/epigenetic regulation, and stress-integrated PTMsβ€”highlighting why pharmacological modulation requires precision and biomarker guidance (hasan2025moleculartargetsof pages 2-4, shakya2024targetingnrf2driven pages 22-27).

5) Relevant statistics and disease data (recent studies)
- Somatic mutation hotspots and prevalence: NFE2L2 gain-of-function mutations cluster in exon 2 affecting DLG/ETGE motifs, conferring KEAP1-evasion; across TCGA lung cohorts, squamous cancers exhibit high pathway alteration burdens, with reported frequencies on the order of ~20–30% across KEAP1/NFE2L2 in LUSC and notable, though lower, rates in LUAD; KEAP1 and NFE2L2 mutations tend to be mutually exclusive (recent reviews summarizing TCGA analyses) (sparaneo2025decodingthenrf2–notch pages 4-5, sparaneo2025decodingthenrf2–notch pages 2-4, oskomic2025keap1nrf2interactionin pages 2-4). These alterations often correlate with poor prognosis in lung and other cancers, though effects can be context-dependent (sparaneo2025decodingthenrf2–notch pages 2-4, panda2025nrf2immunobiologyin pages 1-2).
- Immunotherapy associations: Mechanistic and translational analyses indicate constitutive NRF2 activity is associated with impaired responses to anti-PD1 therapy across multiple tumors, via metabolic reprogramming and suppression of cytotoxic immune responses; this motivates biomarker-driven combination approaches (Oncogene, 2025) (panda2025nrf2immunobiologyin pages 1-2).

Molecular mechanism and pathway positioning (precision details)
- KEAP1–NRF2–CUL3 axis: KEAP1’s BTB domain recruits CUL3–RBX1; its Kelch domain recognizes NRF2’s ETGE/DLG in Neh2; stress modifies KEAP1 cysteines (e.g., Cys151, Cys273, Cys288 among many), abrogating ubiquitination and enabling NRF2 nuclear action (hasan2025moleculartargetsof pages 2-4, panda2025nrf2immunobiologyin pages 1-2). The hinge-and-latch model explains differential affinity of ETGE vs DLG sites; electrophiles can shift KEAP1 conformation and E3 geometry (shakya2024targetingnrf2driven pages 22-27, hasan2025moleculartargetsof pages 2-4).
- KEAP1-independent regulation: GSK3-mediated phosphorylation of Neh6 DSGIS/DSAPGS motifs recruits Ξ²-TrCP for CUL1-mediated degradation; PI3K–AKT through GSK3 inhibition stabilizes NRF2. p62/SQSTM1 (phospho-STGE) competes with NRF2 for KEAP1, promoting KEAP1 autophagic turnover and NRF2 stabilization (hasan2025moleculartargetsof pages 2-4, sparaneo2025decodingthenrf2–notch pages 2-4).
- Target gene programs: Antioxidant/detoxification (NQO1, HMOX1, GCL genes), glutathione and NADPH metabolism, proteostasis/autophagy support, and adaptive stress resistance; ARE consensus typically TGACnnnGC in sMAF:NRF2-bound promoters/enhancers (shakya2024targetingnrf2driven pages 22-27, shakya2024targetingnrf2driven pages 18-22).

Subcellular localization and site of action
- Basal state: cytoplasmic NRF2 tethered to KEAP1–CUL3–RBX1 and rapidly degraded (sparaneo2025decodingthenrf2–notch pages 4-5, sparaneo2025decodingthenrf2–notch pages 2-4).
- Activated state: stabilized NRF2 accumulates in the nucleus to drive ARE-dependent transcription with small MAF partners (sparaneo2025decodingthenrf2–notch pages 2-4).

Therapeutic landscape and implementation notes
- Activators in the clinic: DMF (MS) and omaveloxolone (Friedreich’s ataxia) validate therapeutic NRF2 activation; development of non-electrophilic modulators and delivery/formulation strategies continues, but selective inhibition of NRF2 in cancer remains an unmet need (oskomic2025keap1nrf2interactionin pages 2-4, panda2025nrf2immunobiologyin pages 1-2).
- Safety and context: In kidney disease, potent NRF2 activation has shown renal hemodynamic effects and safety trade-offs, arguing for precision dosing and disease-stage tailoring; oncology settings require strategies that mitigate NRF2-driven resistance (oskomic2025keap1nrf2interactionin pages 2-4, panda2025nrf2immunobiologyin pages 1-2).

Verification of identity and domain/family alignment
- The literature consistently describes human NRF2 (NFE2L2) as a CNC-bZIP transcription factor with Neh1–Neh7 domains, KEAP1-binding ETGE/DLG motifs in Neh2, and Ξ²-TrCP degrons in Neh6, fully aligning with the UniProt-provided identity, organism (Homo sapiens), and domain annotations (chen2024keap1nrf2pathwaya pages 4-5, shakya2024targetingnrf2driven pages 22-27, sparaneo2025decodingthenrf2–notch pages 2-4).

Key references with URLs and dates
- Chen F et al., 2024, Frontiers in Oncology. β€œKeap1–Nrf2 pathway: a key mechanism in the occurrence and development of cancer.” DOI: 10.3389/fonc.2024.1381467. URL: https://doi.org/10.3389/fonc.2024.1381467 (chen2024keap1nrf2pathwaya pages 4-5).
- Shakya A., 2024. β€œTargeting Nrf2 driven pathways in cancer: mechanisms of resistance and therapeutic opportunities.” URL: not available in excerpt; domain/mechanism synthesis used (shakya2024targetingnrf2driven pages 22-27, shakya2024targetingnrf2driven pages 18-22).
- Hasan SK et al., 2025, Cells. β€œMolecular targets of oxidative stress: focus on NRF2 function in leukemia and other cancers.” DOI: 10.3390/cells14100713. URL: https://doi.org/10.3390/cells14100713 (hasan2025moleculartargetsof pages 2-4).
- Sparaneo A. et al., 2025, Antioxidants. β€œDecoding the NRF2–NOTCH crosstalk in lung cancerβ€”An Update.” DOI: 10.3390/antiox14060657. URL: https://doi.org/10.3390/antiox14060657 (sparaneo2025decodingthenrf2–notch pages 4-5, sparaneo2025decodingthenrf2–notch pages 2-4).
- Panda H. et al., 2025, Oncogene. β€œNRF2 immunobiology in cancer: implications for immunotherapy and therapeutic targeting.” DOI: 10.1038/s41388-025-03560-4. URL: https://doi.org/10.1038/s41388-025-03560-4 (panda2025nrf2immunobiologyin pages 1-2).
- OskomiΔ‡ M. et al., 2025, Cancers. β€œKEAP1–NRF2 interaction in cancer: competitive interactors and their role in carcinogenesis.” DOI: 10.3390/cancers17030447. URL: https://doi.org/10.3390/cancers17030447 (oskomic2025keap1nrf2interactionin pages 2-4).

Notes on evidence limits
- Where precise numerical frequencies or interventional outcomes are needed (e.g., per-cancer mutation rates or trial statistics), the above reviews summarize TCGA and clinical experiences; figures should be re-verified directly in the primary TCGA or trial publications when making decisions. Nonetheless, the cited sources consolidate the most recent mechanistic and translational consensus (sparaneo2025decodingthenrf2–notch pages 4-5, panda2025nrf2immunobiologyin pages 1-2, oskomic2025keap1nrf2interactionin pages 2-4).

References

  1. (chen2024keap1nrf2pathwaya pages 4-5): Feilong Chen, Mei Xiao, Shaofan Hu, and Meng Wang. Keap1-nrf2 pathway: a key mechanism in the occurrence and development of cancer. Frontiers in Oncology, Apr 2024. URL: https://doi.org/10.3389/fonc.2024.1381467, doi:10.3389/fonc.2024.1381467. This article has 56 citations and is from a poor quality or predatory journal.

  2. (shakya2024targetingnrf2driven pages 22-27): A Shakya. Targeting nrf2 driven pathways in cancer: mechanisms of resistance and therapeutic opportunities. Unknown journal, 2024.

  3. (hasan2025moleculartargetsof pages 2-4): Syed K. Hasan, Sundarraj Jayakumar, Eliezer Espina Barroso, Anup Jha, Gianfranco Catalano, Santosh K. Sandur, and Nelida I. Noguera. Molecular targets of oxidative stress: focus on nuclear factor erythroid 2–related factor 2 function in leukemia and other cancers. Cells, 14:713, May 2025. URL: https://doi.org/10.3390/cells14100713, doi:10.3390/cells14100713. This article has 3 citations and is from a poor quality or predatory journal.

  4. (sparaneo2025decodingthenrf2–notch pages 2-4): Angelo Sparaneo, Filippo Torrisi, Floriana D’Angeli, Giovanni Giurdanella, Sara Bravaccini, Lucia Anna Muscarella, and Federico Pio Fabrizio. Decoding the nrf2–notch crosstalk in lung cancerβ€”an update. Antioxidants, 14:657, May 2025. URL: https://doi.org/10.3390/antiox14060657, doi:10.3390/antiox14060657. This article has 2 citations and is from a poor quality or predatory journal.

  5. (sparaneo2025decodingthenrf2–notch pages 4-5): Angelo Sparaneo, Filippo Torrisi, Floriana D’Angeli, Giovanni Giurdanella, Sara Bravaccini, Lucia Anna Muscarella, and Federico Pio Fabrizio. Decoding the nrf2–notch crosstalk in lung cancerβ€”an update. Antioxidants, 14:657, May 2025. URL: https://doi.org/10.3390/antiox14060657, doi:10.3390/antiox14060657. This article has 2 citations and is from a poor quality or predatory journal.

  6. (oskomic2025keap1nrf2interactionin pages 2-4): Marina Oskomić, Antonija Tomić, Lea Barbarić, Antonia Matić, Domagoj Christian Kindl, and Mihaela Matovina. Keap1-nrf2 interaction in cancer: competitive interactors and their role in carcinogenesis. Cancers, 17:447, Jan 2025. URL: https://doi.org/10.3390/cancers17030447, doi:10.3390/cancers17030447. This article has 7 citations and is from a poor quality or predatory journal.

  7. (panda2025nrf2immunobiologyin pages 1-2): Harit Panda, Natalie G. Rowland, Caroline M. Krall, Brittany M. Bowman, Michael B. Major, and Paul Zolkind. Nrf2 immunobiology in cancer: implications for immunotherapy and therapeutic targeting. Oncogene, 44:3641-3651, Sep 2025. URL: https://doi.org/10.1038/s41388-025-03560-4, doi:10.1038/s41388-025-03560-4. This article has 4 citations and is from a domain leading peer-reviewed journal.

  8. (shakya2024targetingnrf2driven pages 18-22): A Shakya. Targeting nrf2 driven pathways in cancer: mechanisms of resistance and therapeutic opportunities. Unknown journal, 2024.

Citations

  1. hasan2025moleculartargetsof pages 2-4
  2. https://doi.org/10.3389/fonc.2024.1381467
  3. https://doi.org/10.3390/cells14100713
  4. https://doi.org/10.3390/antiox14060657
  5. https://doi.org/10.1038/s41388-025-03560-4
  6. https://doi.org/10.3390/cancers17030447
  7. https://doi.org/10.3389/fonc.2024.1381467,
  8. https://doi.org/10.3390/cells14100713,
  9. https://doi.org/10.3390/antiox14060657,
  10. https://doi.org/10.3390/cancers17030447,
  11. https://doi.org/10.1038/s41388-025-03560-4,

Bioreason Rl Review

(NFE2L2-bioreason-rl-review.md)

BioReason-Pro RL Review: NFE2L2 (human)

Source: NFE2L2-deep-research-bioreason-rl.md

  • Correctness: 3/5
  • Completeness: 3/5

Functional Summary Review

The BioReason functional summary states:

A nuclear, dimeric transcription regulator that uses a C-terminal basic leucine zipper module to bind specific DNA elements and control RNA polymerase II-dependent transcription programs. Its Maf-type dimerization surface favors heterodimer formation that stabilizes promoter occupancy at regulatory elements governing erythroid and stress-adaptive gene networks. Operating in the nucleus, it assembles with partner bZIP factors and co-regulators to fine-tune chromatin-associated transcriptional outputs.

The identification of NFE2L2 (NRF2) as a CNC-bZIP transcription factor that heterodimerizes with small Maf proteins is correct. The DNA binding, dimerization, and nuclear localization are all accurate and match the curated review.

However, BioReason significantly mischaracterizes the primary biological role. The summary emphasizes "erythroid gene networks" as a primary function, which is actually the role of NFE2 (NF-E2 p45), not NFE2L2/NRF2. The curated review describes NFE2L2 as "the master transcriptional regulator of the antioxidant response" that binds antioxidant response elements (AREs) to induce cytoprotective genes including phase II detoxification enzymes, antioxidant proteins, and drug efflux transporters. The review specifically notes NRF2's role in:

  1. Response to oxidative stress (GO:0006979)
  2. Regulation of response to reactive oxygen species
  3. KEAP1-mediated ubiquitin-dependent degradation
  4. Cellular detoxification
  5. Protection against ferroptosis

BioReason mentions "stress-adaptive" gene networks in passing, but the dominant framing around "erythroid programs" is misleading. While the CNC-bZIP family includes erythroid regulators (NFE2, NRF1), NRF2's defining function is the antioxidant/electrophile response.

Comparison with interpro2go:

The interpro2go annotations from the bZIP and Skn-1-like domains would map to DNA binding and transcription factor activity, which BioReason correctly captures. The family-level annotation (IPR047167, Nuclear Factor Erythroid-derived 2-like) does contain "erythroid" in the name, which likely biased BioReason toward the erythroid emphasis. This represents a case where interpro2go family naming misleads the model's biological process inference.

Notes on thinking trace

The trace correctly identifies the Skn-1/Nrf-like DNA-binding module and Maf-type bZIP. The prediction of small Maf partners (MAFK, MAFF, MAFG) is accurate. However, the "erythroid" emphasis appears to stem from the family name rather than functional evidence, demonstrating a weakness in pure domain-based reasoning.

πŸ“„ View Raw YAML

 
id: Q16236
gene_symbol: NFE2L2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:20452972
      supporting_text: 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.
    - reference_id: file:human/NFE2L2/NFE2L2-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: NRF2 is the prototypical ARE-binding transcription factor that activates Pol II-mediated transcription of cytoprotective genes upon nuclear translocation.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:20452972
      supporting_text: 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.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: NRF2 translocates to the nucleus upon stabilization (following electrophile exposure or autophagy-mediated KEAP1 sequestration) where it binds AREs and activates transcription.
    action: ACCEPT
    reason: Nuclear localization is essential for NRF2's transcription factor function. Under stress conditions, NRF2 accumulates in the nucleus to exert its transcriptional activity.
    supported_by:
    - reference_id: PMID:15601839
      supporting_text: BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: NRF2 is a master regulator of transcription, activating hundreds of genes containing AREs in their regulatory regions upon oxidative or electrophilic stress.
    action: ACCEPT
    reason: This biological process is the primary function of NRF2. The IBA annotation captures the conserved regulatory role across species.
    supported_by:
    - reference_id: PMID:20452972
      supporting_text: 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.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:15601839
      supporting_text: BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase.
    - reference_id: PMID:26403645
      supporting_text: Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells.
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Duplicate of IBA annotation. Automated inference from ortholog and InterPro data confirms the DNA-binding function.
    action: ACCEPT
    reason: Consistent with IBA annotation and well-supported by NRF2's bZIP domain structure.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: General DNA binding term inferred from InterPro bZIP domain annotations.
    action: ACCEPT
    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.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Inferred from bZIP domain annotations. NRF2 is a classic DNA-binding transcription factor.
    action: ACCEPT
    reason: Core molecular function of NRF2, well-established through domain analysis and experimental evidence.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Automated inference of nuclear localization from orthologs and subcellular location data.
    action: ACCEPT
    reason: Consistent with IBA and experimental IDA annotations. Nuclear localization is essential for NRF2 transcription factor function.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: NRF2 is cytosolic when bound to KEAP1 under basal conditions.
    action: ACCEPT
    reason: Accurate annotation. Under normal conditions, KEAP1 sequesters NRF2 in the cytosol for ubiquitin-mediated degradation.
- term:
    id: GO:0006351
    label: DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Inferred from UniProt keyword mapping. NRF2 is involved in transcription.
    action: ACCEPT
    reason: Valid general annotation. More specific annotations about transcription regulation are also present.
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Inferred from InterPro bZIP domain annotations.
    action: ACCEPT
    reason: NRF2 is a transcriptional activator. This general term is appropriate given the more specific IBA annotation for Pol II regulation.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Inferred from InterPro NFE2-like family annotation.
    action: ACCEPT
    reason: Consistent with IBA annotation for this process. NRF2 specifically regulates Pol II transcription.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16888629
  review:
    summary: Structural study demonstrating NRF2 ETGE peptide binding to KEAP1 Kelch domain. This shows specific interaction with KEAP1 (Q14145).
    action: MODIFY
    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_replacement_terms:
    - id: GO:0031625
      label: ubiquitin protein ligase binding
    supported_by:
    - reference_id: PMID:16888629
      supporting_text: Aug 3. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17015834
  review:
    summary: DJ-1 stabilizes NRF2 by preventing KEAP1-mediated degradation. Shows interaction with both KEAP1 (Q14145) in the context of NRF2 stabilization.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:17015834
      supporting_text: DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18048326
  review:
    summary: Retinoic acid receptor alpha (RARA) inhibits NRF2 transcriptional activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Interaction with RARA represents a regulatory mechanism, but 'protein binding' is uninformative. Context-specific terms would be more appropriate.
    supported_by:
    - reference_id: PMID:18048326
      supporting_text: Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18692475
  review:
    summary: C. elegans interactome study showing interaction with MAFG (O15525).
    action: ACCEPT
    reason: Interaction with small MAF proteins (MAFG, MAFK, MAFF) is essential for NRF2 DNA binding and transcriptional activation. These are obligate heterodimerization partners.
    supported_by:
    - reference_id: PMID:18692475
      supporting_text: A protein domain-based interactome network for C.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18757741
  review:
    summary: Cancer-related NRF2 mutations impair KEAP1 recognition. Shows NRF2-KEAP1 interaction.
    action: MODIFY
    reason: This is the functionally critical KEAP1 binding that targets NRF2 for degradation.
    proposed_replacement_terms:
    - id: GO:0031625
      label: ubiquitin protein ligase binding
    supported_by:
    - reference_id: PMID:18757741
      supporting_text: Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19706542
  review:
    summary: Nitric oxide activation of KEAP1/NRF2 signaling pathway in colon carcinoma cells.
    action: MARK_AS_OVER_ANNOTATED
    reason: Another KEAP1 interaction study. The regulatory nature is not captured by generic protein binding term.
    supported_by:
    - reference_id: PMID:19706542
      supporting_text: Nitric oxide activation of Keap1/Nrf2 signaling in human colon carcinoma cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  review:
    summary: Human liver protein interactome study showing NRF2 interactions with MAFG, MAFK, KEAP1.
    action: ACCEPT
    reason: High-throughput interactome study confirming known interactions. Small MAF proteins are essential partners.
    supported_by:
    - reference_id: PMID:21988832
      supporting_text: Toward an understanding of the protein interaction network of the human liver.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23661758
  review:
    summary: Networks of bZIP protein-protein interactions. Shows NRF2 interactions with MAFG, ATF4, and MAFF.
    action: ACCEPT
    reason: Interactions with bZIP family members including small MAFs and ATF4 are central to NRF2 function in stress response.
    supported_by:
    - reference_id: PMID:23661758
      supporting_text: Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: Proteome-scale human interactome network showing NRF2 interactions.
    action: ACCEPT
    reason: Large-scale validation of NRF2 protein interactions.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25684205
  review:
    summary: CUL3-KBTBD6/KBTBD7 ubiquitin ligase study mentioning KEAP1 interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: Focus is on CUL3 substrate adaptors; NRF2-KEAP1 interaction is tangential.
    supported_by:
    - reference_id: PMID:25684205
      supporting_text: 2015 Feb 12. CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP proteins to spatially restrict TIAM1-RAC1 signaling.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26700459
  review:
    summary: Proteasome inhibition induces NRF2/ATF4 interaction.
    action: ACCEPT
    reason: ATF4 is a stress-responsive bZIP transcription factor that partners with NRF2 in integrated stress response.
    supported_by:
    - reference_id: PMID:26700459
      supporting_text: Involvement of Nrf2 in proteasome inhibition-mediated induction of ORP150 in thyroid cancer cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28777872
  review:
    summary: "PML-RARΞ± activates NRF2 through direct interaction."
    action: ACCEPT
    reason: Shows NRF2 regulation in leukemia context.
    supported_by:
    - reference_id: PMID:28777872
      supporting_text: Aug 21. The short isoform of PML-RARΞ± activates the NRF2/HO-1 pathway through a direct interaction with NRF2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29792731
  review:
    summary: APR3 modulates oxidative stress in retinal epithelial cells through NRF2.
    action: MARK_AS_OVER_ANNOTATED
    reason: Context-specific interaction that does not define core NRF2 function.
    supported_by:
    - reference_id: PMID:29792731
      supporting_text: of print. APR3 modulates oxidative stress and mitochondrial function in ARPE-19 cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31169361
  review:
    summary: Peptidomic display study on KEAP1 interaction with NRF2-derived peptides.
    action: MODIFY
    reason: This is specifically about the KEAP1 E3 ligase interaction.
    proposed_replacement_terms:
    - id: GO:0031625
      label: ubiquitin protein ligase binding
    supported_by:
    - reference_id: PMID:31169361
      supporting_text: 2019 Jun 6. A Case Study on the Keap1 Interaction with Peptide Sequence Epitopes Selected by the Peptidomic mRNA Display.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31262713
  review:
    summary: FAM129B competes with NRF2 for KEAP1 binding.
    action: MODIFY
    reason: Demonstrates the competitive binding to KEAP1 E3 ligase.
    proposed_replacement_terms:
    - id: GO:0031625
      label: ubiquitin protein ligase binding
    supported_by:
    - reference_id: PMID:31262713
      supporting_text: Jun 28. FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: Genetic variants disrupting protein interactions. TNNT1 interaction shown.
    action: MARK_AS_OVER_ANNOTATED
    reason: Interaction with troponin T (TNNT1) is unlikely to be functionally significant for NRF2's transcription factor role.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: Reference map of human binary protein interactome confirming NRF2 interactions with MAFG, MAFK, KDM1A.
    action: ACCEPT
    reason: Confirms essential interactions with small MAF proteins and histone demethylase KDM1A involved in transcriptional regulation.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: Apr 8. A reference map of the human binary protein interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32911434
  review:
    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.
    action: ACCEPT
    reason: Comprehensive interactome study providing validated NRF2 interaction partners that regulate ARE-driven transcription.
    supported_by:
    - reference_id: PMID:32911434
      supporting_text: Aug 20. A functionally defined high-density NRF2 interactome reveals new conditional regulators of ARE transactivation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Dual proteome-scale networks showing cell-specific NRF2 interactome remodeling.
    action: ACCEPT
    reason: Shows context-dependent NRF2 interactions with MAFK, MAFF in different cell types.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34591642
  review:
    summary: Protein network in head and neck cancer showing NRF2 interactions.
    action: ACCEPT
    reason: Cancer-relevant interaction network confirming NRF2 partners.
    supported_by:
    - reference_id: PMID:34591642
      supporting_text: Oct 1. A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35512704
  review:
    summary: Mutation-directed neo-interactions in cancer. Shows mutant NRF2-KEAP1 interactions.
    action: ACCEPT
    reason: Important for understanding cancer-specific NRF2 pathway dysregulation.
    supported_by:
    - reference_id: PMID:35512704
      supporting_text: 2022 May 4. Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36442525
  review:
    summary: ARD1 (NAA10) stabilizes NRF2 through direct interaction and promotes colon cancer.
    action: ACCEPT
    reason: Shows regulatory interaction with NAA10 acetyltransferase affecting NRF2 stability.
    supported_by:
    - reference_id: PMID:36442525
      supporting_text: Nov 25. ARD1 stabilizes NRF2 through direct interaction and promotes colon cancer progression.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37187359
  review:
    summary: Geniposide ameliorates ulcerative colitis via KEAP1-NRF2 signaling.
    action: MARK_AS_OVER_ANNOTATED
    reason: Pharmacological study; KEAP1-NRF2 interaction is tangential to main finding.
    supported_by:
    - reference_id: PMID:37187359
      supporting_text: 2023 May 13. Geniposide ameliorates dextran sulfate sodium-induced ulcerative colitis via KEAP1-Nrf2 signaling pathway.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:38891776
  review:
    summary: Pin1 involved in neural tube closure. Shows NRF2-PIN1 interaction.
    action: ACCEPT
    reason: PIN1 is a peptidyl-prolyl isomerase that can regulate NRF2 activity through conformational changes.
    supported_by:
    - reference_id: PMID:38891776
      supporting_text: Pin1 Downregulation Is Involved in Excess Retinoic Acid-Induced Failure of Neural Tube Closure.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:39009827
  review:
    summary: Disease mutations affecting motif-based interactome. KEAP1 interaction affected by NRF2 mutations.
    action: ACCEPT
    reason: Important for understanding how disease mutations in NRF2 ETGE/DLG motifs disrupt KEAP1 binding.
    supported_by:
    - reference_id: PMID:39009827
      supporting_text: 2024 Jul 15. Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 associates with chromatin at ARE sites to activate transcription.
    action: ACCEPT
    reason: As a DNA-binding transcription factor, NRF2 must associate with chromatin to exert its function.
- term:
    id: GO:0000976
    label: transcription cis-regulatory region binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: NRF2 binds to ARE cis-regulatory elements in target gene promoters.
    action: ACCEPT
    reason: Well-established molecular function of NRF2.
- term:
    id: GO:0001221
    label: transcription coregulator binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 interacts with coactivators like CBP/p300 to enhance transcription.
    action: ACCEPT
    reason: NRF2 recruits transcriptional coactivators to AREs for robust gene activation.
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 specifically activates Pol II-mediated transcription of target genes.
    action: ACCEPT
    reason: Core molecular function of NRF2 as a transcriptional activator.
- term:
    id: GO:0002931
    label: response to ischemia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 activation provides cytoprotection during ischemia/reperfusion injury.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 is located in the cytoplasm when bound to KEAP1.
    action: ACCEPT
    reason: Accurate. Under basal conditions, KEAP1 retains NRF2 in the cytoplasm.
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 is activated by xenobiotic electrophiles and induces detoxification genes.
    action: ACCEPT
    reason: Core function of NRF2. Electrophilic xenobiotics modify KEAP1 cysteines, stabilizing NRF2 to induce phase II detoxifying enzymes.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: NRF2 positively regulates expression of ARE-containing target genes.
    action: ACCEPT
    reason: Core function as a transcriptional activator.
- term:
    id: GO:0010667
    label: negative regulation of cardiac muscle cell apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 protects cardiomyocytes from oxidative stress-induced apoptosis.
    action: KEEP_AS_NON_CORE
    reason: Cardioprotection is a tissue-specific downstream effect of NRF2's antioxidant program.
- term:
    id: GO:0010976
    label: positive regulation of neuron projection development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 supports neuronal development through redox homeostasis.
    action: KEEP_AS_NON_CORE
    reason: Neuronal development is a context-specific effect, not a core NRF2 function.
- term:
    id: GO:0030194
    label: positive regulation of blood coagulation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Inferred from mouse orthologs. Connection to coagulation is indirect.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is likely an indirect effect or based on limited evidence. Blood coagulation regulation is not a well-established NRF2 function.
- term:
    id: GO:0032993
    label: protein-DNA complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 forms protein-DNA complexes with small MAF proteins at AREs.
    action: ACCEPT
    reason: NRF2:sMAF heterodimers bound to ARE DNA represent the active transcription complex.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Duplicate of IBA annotation for oxidative stress response.
    action: ACCEPT
    reason: Core function of NRF2 confirmed by multiple evidence types.
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 is activated during ER stress as part of the unfolded protein response.
    action: ACCEPT
    reason: ER stress activates NRF2 through PERK-mediated phosphorylation, connecting the antioxidant response to proteostasis.
- term:
    id: GO:0036499
    label: PERK-mediated unfolded protein response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 is phosphorylated by PERK during UPR, promoting nuclear translocation.
    action: ACCEPT
    reason: PERK phosphorylation of NRF2 is a key mechanism connecting ER stress to antioxidant defense.
- term:
    id: GO:0042149
    label: cellular response to glucose starvation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 is activated during metabolic stress including glucose deprivation.
    action: ACCEPT
    reason: Metabolic stress activates NRF2 to maintain redox homeostasis.
- term:
    id: GO:0043536
    label: positive regulation of blood vessel endothelial cell migration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 promotes angiogenesis in part through endothelial cell migration.
    action: KEEP_AS_NON_CORE
    reason: Angiogenesis promotion is a downstream effect of NRF2 in vascular biology contexts.
- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 binds specifically to ARE consensus sequences (TGACnnnGC).
    action: ACCEPT
    reason: Core molecular function of NRF2 as an ARE-binding transcription factor.
- term:
    id: GO:0045088
    label: regulation of innate immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 modulates innate immunity by suppressing pro-inflammatory gene expression and regulating STING signaling.
    action: ACCEPT
    reason: NRF2 plays an important role in inflammatory regulation by inhibiting NF-kB signaling and suppressing cytokine production.
- term:
    id: GO:0045454
    label: cell redox homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: NRF2 maintains cellular redox balance by inducing antioxidant genes.
    action: ACCEPT
    reason: Core function of NRF2. Target genes include GCLC, GCLM, TXN, PRDX, NQO1.
- term:
    id: GO:0045766
    label: positive regulation of angiogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 promotes angiogenesis through VEGF pathway regulation.
    action: KEEP_AS_NON_CORE
    reason: Pro-angiogenic effect is context-dependent, not a core NRF2 function.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: NRF2 activates Pol II-mediated transcription of target genes.
    action: ACCEPT
    reason: Core function as a transcriptional activator.
- term:
    id: GO:0046223
    label: aflatoxin catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 induces enzymes that detoxify aflatoxin and other xenobiotics.
    action: KEEP_AS_NON_CORE
    reason: Aflatoxin detoxification is a specific example of NRF2's broader xenobiotic detoxification function.
- term:
    id: GO:0046326
    label: positive regulation of D-glucose import across plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 regulates glucose transporter expression.
    action: KEEP_AS_NON_CORE
    reason: Metabolic regulation is a downstream effect of NRF2, not a core function.
- term:
    id: GO:0061431
    label: cellular response to methionine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 responds to methionine-related stress (possibly through homocysteine).
    action: KEEP_AS_NON_CORE
    reason: Specific metabolic response, not a core NRF2 function.
- term:
    id: GO:0071356
    label: cellular response to tumor necrosis factor
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 mediates cellular responses to TNF through anti-inflammatory mechanisms.
    action: ACCEPT
    reason: NRF2 cross-talks with inflammatory signaling pathways and can be activated by TNF-induced oxidative stress.
- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 is activated by hypoxia and provides cytoprotection.
    action: ACCEPT
    reason: Hypoxia activates NRF2 through ROS generation and HIF crosstalk.
- term:
    id: GO:1900038
    label: negative regulation of cellular response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 can modulate hypoxic responses through HIF pathway crosstalk.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory effect, not a primary NRF2 function.
- term:
    id: GO:1902037
    label: negative regulation of hematopoietic stem cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 affects HSC differentiation through redox regulation.
    action: KEEP_AS_NON_CORE
    reason: Hematopoietic effects are tissue-specific downstream consequences.
- term:
    id: GO:1903788
    label: positive regulation of glutathione biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 induces GCLC and GCLM, the rate-limiting enzymes for glutathione synthesis.
    action: ACCEPT
    reason: Core function of NRF2. Glutathione synthesis genes are canonical NRF2 targets.
- term:
    id: GO:1904385
    label: cellular response to angiotensin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Angiotensin II induces oxidative stress that activates NRF2.
    action: KEEP_AS_NON_CORE
    reason: Cardiovascular-specific stimulus response, not a core NRF2 function.
- term:
    id: GO:1904753
    label: negative regulation of vascular associated smooth muscle cell migration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 affects smooth muscle cell behavior in vascular contexts.
    action: KEEP_AS_NON_CORE
    reason: Vascular biology-specific effect, not a core NRF2 function.
- term:
    id: GO:2000121
    label: regulation of removal of superoxide radicals
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 induces SOD and other enzymes that remove superoxide.
    action: ACCEPT
    reason: Core function as part of the antioxidant response.
- term:
    id: GO:2000379
    label: positive regulation of reactive oxygen species metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NRF2 regulates ROS metabolism through induction of antioxidant enzymes.
    action: ACCEPT
    reason: Core function. NRF2 coordinates the cellular ROS detoxification machinery.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Immunofluorescence-based localization from Human Protein Atlas showing nuclear NRF2.
    action: ACCEPT
    reason: Nuclear localization is essential for NRF2 transcription factor function.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Immunofluorescence showing cytosolic NRF2 (likely under basal conditions with KEAP1).
    action: ACCEPT
    reason: Cytosolic localization reflects KEAP1-bound NRF2 under unstressed conditions.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  original_reference_id: PMID:23661758
  review:
    summary: bZIP protein interaction networks study noting NRF2 nuclear function.
    action: ACCEPT
    reason: Consistent with multiple other annotations for nuclear localization.
    supported_by:
    - reference_id: PMID:23661758
      supporting_text: Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: NAS
  original_reference_id: PMID:23661758
  review:
    summary: bZIP transcription factor network study.
    action: ACCEPT
    reason: Consistent with IBA and other annotations for this process.
    supported_by:
    - reference_id: PMID:23661758
      supporting_text: Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
- term:
    id: GO:0140467
    label: integrated stress response signaling
  evidence_type: NAS
  original_reference_id: PMID:28566324
  review:
    summary: ATF4-NRF2 complex participates in integrated stress response.
    action: ACCEPT
    reason: NRF2 is a component of the integrated stress response, working with ATF4 to coordinate cytoprotective gene expression.
    supported_by:
    - reference_id: PMID:28566324
      supporting_text: 2017 May 31. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals.
- term:
    id: GO:0030217
    label: T cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Transferred from mouse ortholog data showing NRF2 role in T cell development.
    action: KEEP_AS_NON_CORE
    reason: T cell effects are tissue-specific and not a primary NRF2 function.
- term:
    id: GO:0006979
    label: response to oxidative stress
  evidence_type: IDA
  original_reference_id: PMID:36075446
  review:
    summary: FOXO4 modulates NRF2 signaling in lens epithelial cells during oxidative stress.
    action: ACCEPT
    reason: Core function of NRF2 as the master oxidative stress response transcription factor.
    supported_by:
    - reference_id: PMID:36075446
      supporting_text: 2022 Sep 6. FOXO4 mediates resistance to oxidative stress in lens epithelial cells by modulating the TRIM25/Nrf2 signaling.
- term:
    id: GO:0000976
    label: transcription cis-regulatory region binding
  evidence_type: IDA
  original_reference_id: PMID:17015834
  review:
    summary: DJ-1 stabilizes NRF2, allowing it to bind cis-regulatory AREs.
    action: ACCEPT
    reason: Core molecular function of NRF2.
    supported_by:
    - reference_id: PMID:17015834
      supporting_text: DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2.
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  evidence_type: IDA
  original_reference_id: PMID:17015834
  review:
    summary: NRF2 activates Pol II transcription from ARE-containing promoters.
    action: ACCEPT
    reason: Core molecular function demonstrated through DJ-1 stabilization experiments.
    supported_by:
    - reference_id: PMID:17015834
      supporting_text: DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2.
- term:
    id: GO:0110076
    label: negative regulation of ferroptosis
  evidence_type: IMP
  original_reference_id: PMID:26403645
  review:
    summary: Landmark study demonstrating NRF2 protects hepatocellular carcinoma cells against ferroptosis through induction of NQO1, HMOX1, and FTH1.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:26403645
      supporting_text: Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells.
    - reference_id: PMID:26403645
- term:
    id: GO:1904294
    label: positive regulation of ERAD pathway
  evidence_type: TAS
  original_reference_id: PMID:23800989
  review:
    summary: NRF2 induces proteasome subunit genes and ER-associated degradation components.
    action: ACCEPT
    reason: NRF2 coordinates proteostasis by inducing proteasome genes and ERAD components.
    supported_by:
    - reference_id: PMID:23800989
      supporting_text: 'Epub 2013 Jun 26. Nrf2 and Nrf1 signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy.'
- term:
    id: GO:2000060
    label: positive regulation of ubiquitin-dependent protein catabolic process
  evidence_type: TAS
  original_reference_id: PMID:23800989
  review:
    summary: NRF2 promotes proteasome activity through induction of proteasome subunit genes.
    action: ACCEPT
    reason: Connection to proteostasis through transcriptional activation of proteasome genes.
    supported_by:
    - reference_id: PMID:23800989
      supporting_text: 'Epub 2013 Jun 26. Nrf2 and Nrf1 signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy.'
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:23043106
  review:
    summary: Laminar flow activates ERK5 leading to NRF2-mediated transcription in endothelium.
    action: ACCEPT
    reason: Core function of NRF2 as a transcriptional activator.
    supported_by:
    - reference_id: PMID:23043106
      supporting_text: 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:24844779
  review:
    summary: Hypoxia-responsive miR-101 promotes NRF2-mediated HO-1 induction.
    action: ACCEPT
    reason: Core transcriptional activation function of NRF2.
    supported_by:
    - reference_id: PMID:24844779
      supporting_text: Epub 2014 Jul 29. Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3.
- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IMP
  original_reference_id: PMID:24844779
  review:
    summary: NRF2 is activated during hypoxia and promotes cytoprotective gene expression.
    action: ACCEPT
    reason: Hypoxia activates NRF2 through ROS and other mechanisms.
    supported_by:
    - reference_id: PMID:24844779
      supporting_text: Epub 2014 Jul 29. Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3.
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  evidence_type: IMP
  original_reference_id: PMID:22492997
  review:
    summary: DJ-1 induces thioredoxin 1 expression through NRF2 pathway.
    action: ACCEPT
    reason: Core molecular function of NRF2.
    supported_by:
    - reference_id: PMID:22492997
      supporting_text: Apr 5. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:22492997
  review:
    summary: NRF2 activates TXN1 transcription through ARE binding.
    action: ACCEPT
    reason: Core function demonstrated through TXN1 as a target gene.
    supported_by:
    - reference_id: PMID:22492997
      supporting_text: Apr 5. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway.
- term:
    id: GO:0070301
    label: cellular response to hydrogen peroxide
  evidence_type: IGI
  original_reference_id: PMID:22492997
  review:
    summary: DJ-1 and NRF2 cooperate in H2O2 response through TXN1 induction.
    action: ACCEPT
    reason: H2O2 is a key ROS that activates NRF2 through KEAP1 cysteine modification.
    supported_by:
    - reference_id: PMID:22492997
      supporting_text: Apr 5. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IDA
  original_reference_id: PMID:36075446
  review:
    summary: FOXO4-NRF2 signaling in lens epithelial oxidative stress response.
    action: ACCEPT
    reason: Core function of NRF2.
    supported_by:
    - reference_id: PMID:36075446
      supporting_text: 2022 Sep 6. FOXO4 mediates resistance to oxidative stress in lens epithelial cells by modulating the TRIM25/Nrf2 signaling.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9796067
  review:
    summary: PRKAA2 phosphorylates nuclear NRF2.
    action: ACCEPT
    reason: Nuclear localization essential for NRF2 function.
- term:
    id: GO:0016592
    label: mediator complex
  evidence_type: EXP
  original_reference_id: PMID:32727915
  review:
    summary: NRF2 interacts with Mediator complex components for transcriptional activation.
    action: ACCEPT
    reason: NRF2 recruits Mediator complex to enhance transcription of target genes.
    supported_by:
    - reference_id: PMID:32727915
      supporting_text: Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IEP
  original_reference_id: PMID:16888629
  review:
    summary: NRF2 ETGE motif binds KEAP1 Kelch domain, targeting NRF2 for CUL3 E3 ligase complex.
    action: ACCEPT
    reason: Core regulatory mechanism. The KEAP1-CUL3-RBX1 complex ubiquitinates NRF2.
    supported_by:
    - reference_id: PMID:16888629
      supporting_text: Aug 3. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:24366543
  review:
    summary: Detailed characterization of NRF2 DLGex degron binding to KEAP1.
    action: ACCEPT
    reason: Characterizes the low-affinity DLG binding site for KEAP1.
    supported_by:
    - reference_id: PMID:24366543
      supporting_text: Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:32727915
  review:
    summary: NRF2 activation ameliorates oxidative stress in polycystic kidney disease.
    action: ACCEPT
    reason: Core function as a transcriptional activator.
    supported_by:
    - reference_id: PMID:32727915
      supporting_text: Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease.
- term:
    id: GO:0140693
    label: molecular condensate scaffold activity
  evidence_type: IDA
  original_reference_id: PMID:32727915
  review:
    summary: NRF2 can form biomolecular condensates involved in transcriptional regulation.
    action: ACCEPT
    reason: Novel aspect of NRF2 function in transcriptional regulation through phase separation.
    supported_by:
    - reference_id: PMID:32727915
      supporting_text: Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease.
- term:
    id: GO:1900407
    label: regulation of cellular response to oxidative stress
  evidence_type: EXP
  original_reference_id: PMID:34299054
  review:
    summary: Study on NRF2 intrinsic disorder and its role in oxidative stress regulation.
    action: ACCEPT
    reason: Core function of NRF2 as the master regulator of oxidative stress response.
    supported_by:
    - reference_id: PMID:34299054
      supporting_text: Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8932355
  review:
    summary: 26S proteasome degrades ubiquitinated NRF2 in cytosol.
    action: ACCEPT
    reason: Cytosolic degradation of KEAP1-bound NRF2.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9755505
  review:
    summary: KEAP1:CUL3:RBX1 complex ubiquitinates NRF2 in cytosol.
    action: ACCEPT
    reason: Cytosolic ubiquitination precedes degradation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9755507
  review:
    summary: VCP/p97 complex extracts ubiquitinated NRF2 for degradation.
    action: ACCEPT
    reason: Cytosolic degradation pathway.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9758090
  review:
    summary: Ubiquitinated NRF2 extraction from CRL3 complex.
    action: ACCEPT
    reason: Part of cytosolic degradation mechanism.
- term:
    id: GO:0045088
    label: regulation of innate immune response
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Transferred from mouse ortholog showing NRF2 role in innate immunity.
    action: ACCEPT
    reason: NRF2 regulates innate immunity by suppressing inflammatory cytokine production and modulating STING signaling.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29983246
  review:
    summary: MOTS-c mitochondrial peptide translocates to nucleus and interacts with NRF2.
    action: ACCEPT
    reason: Novel interaction connecting mitochondrial stress signaling to NRF2 activation.
    supported_by:
    - reference_id: PMID:29983246
      supporting_text: 2018 Jul 5. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9796047
  review:
    summary: PRKAA2-regulated nuclear export of NRF2.
    action: ACCEPT
    reason: Nuclear localization for transcription factor activity.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9796047
  review:
    summary: NRF2 in cytosol for export regulation.
    action: ACCEPT
    reason: Cytosolic localization for KEAP1-mediated regulation.
- term:
    id: GO:0000976
    label: transcription cis-regulatory region binding
  evidence_type: IDA
  original_reference_id: PMID:20452972
  review:
    summary: Chromatin immunoprecipitation demonstrating NRF2 binding to ARE in p62 promoter.
    action: ACCEPT
    reason: Core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: PMID:20452972
      supporting_text: 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.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IDA
  original_reference_id: PMID:20452972
  review:
    summary: NRF2 demonstrated to function as ARE-binding transcription factor.
    action: ACCEPT
    reason: Core molecular function.
    supported_by:
    - reference_id: PMID:20452972
      supporting_text: 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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15601839
  review:
    summary: NRF2 interacts with KEAP1 for ubiquitination targeting.
    action: MODIFY
    reason: The specific KEAP1 interaction should be annotated as ubiquitin protein ligase binding.
    proposed_replacement_terms:
    - id: GO:0031625
      label: ubiquitin protein ligase binding
    supported_by:
    - reference_id: PMID:15601839
      supporting_text: BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:15601839
  review:
    summary: NRF2 detected in nucleus upon stabilization.
    action: ACCEPT
    reason: Nuclear localization essential for transcription factor function.
    supported_by:
    - reference_id: PMID:15601839
      supporting_text: BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:15601839
  review:
    summary: NRF2 accumulates in cytoplasm when proteasome is inhibited while KEAP1 is present.
    action: ACCEPT
    reason: Cytoplasmic localization when sequestered by KEAP1.
    supported_by:
    - reference_id: PMID:15601839
      supporting_text: BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Transferred from mouse ortholog (NRF2/NFE2L2).
    action: ACCEPT
    reason: Core function conserved across mammals.
- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:20452972
  review:
    summary: Gel mobility shift assays showing NRF2 sequence-specific binding to ARE.
    action: ACCEPT
    reason: Core molecular function demonstrated with direct binding assays.
    supported_by:
    - reference_id: PMID:20452972
      supporting_text: 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.
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  review:
    summary: NRF2 as a sequence-specific DNA-binding transcription factor associates with chromatin.
    action: ACCEPT
    reason: Appropriate for a DNA-binding transcription factor.
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  review:
    summary: TFClass annotation for NRF2 as a Pol II-specific transcription factor.
    action: ACCEPT
    reason: Core molecular function.
- term:
    id: GO:0045454
    label: cell redox homeostasis
  evidence_type: IMP
  original_reference_id: PMID:29018201
  review:
    summary: Activating NRF2 mutations cause altered cellular redox state in patients with IMDDHH.
    action: ACCEPT
    reason: Core function demonstrated through human disease mutations.
    supported_by:
    - reference_id: PMID:29018201
      supporting_text: Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:27155659
  review:
    summary: NRF2 regulates gene expression during liver regeneration.
    action: ACCEPT
    reason: Core function as a transcriptional activator.
    supported_by:
    - reference_id: PMID:27155659
      supporting_text: Epub 2016 May 7. Hepatitis B virus inhibits insulin receptor signaling and impairs liver regeneration via intracellular retention of the insulin receptor.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9796053
  review:
    summary: PKC phosphorylates NRF2 in cytosol.
    action: ACCEPT
    reason: Cytosolic phosphorylation regulates NRF2 activity.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8932327
  review:
    summary: NRF2 binds KEAP1:NEDD8-CUL3:RBX1 in cytosol.
    action: ACCEPT
    reason: Cytosolic KEAP1 complex interaction.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9712274
  review:
    summary: NRF2 inducers bind KEAP1:CUL3:RBX1:NRF2 in cytosol.
    action: ACCEPT
    reason: Site of electrophile-mediated NRF2 stabilization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9762100
  review:
    summary: MYC and NICD1-dependent NFE2L2 gene expression.
    action: ACCEPT
    reason: Cytosolic presence for regulation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9796046
  review:
    summary: NFkB-dependent NFE2L2 expression.
    action: ACCEPT
    reason: Cytosolic localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9796060
  review:
    summary: NFE2L2-dependent NFE2L2 expression (autoregulation).
    action: ACCEPT
    reason: Cytosolic NRF2 population.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: TAS
  original_reference_id: PMID:22934019
  review:
    summary: ER stress and aging review connecting NRF2 to oxidative stress response.
    action: ACCEPT
    reason: Core function of NRF2.
    supported_by:
    - reference_id: PMID:22934019
      supporting_text: The endoplasmic reticulum stress response in aging and age-related diseases.
- term:
    id: GO:0036499
    label: PERK-mediated unfolded protein response
  evidence_type: TAS
  original_reference_id: PMID:22934019
  review:
    summary: NRF2 is phosphorylated by PERK during UPR.
    action: ACCEPT
    reason: PERK-NRF2 connection links ER stress to antioxidant defense.
    supported_by:
    - reference_id: PMID:22934019
      supporting_text: The endoplasmic reticulum stress response in aging and age-related diseases.
- term:
    id: GO:0036499
    label: PERK-mediated unfolded protein response
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Transferred from mouse ortholog showing PERK phosphorylation of NRF2.
    action: ACCEPT
    reason: Conserved mechanism across mammals.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: NAS
  original_reference_id: PMID:22013210
  review:
    summary: Review connecting UPR to oxidative stress through IRE1 and NRF2.
    action: ACCEPT
    reason: Core function.
    supported_by:
    - reference_id: PMID:22013210
      supporting_text: 'The unfolded protein response: integrating stress signals through the stress sensor IRE1Ξ±.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21597468
  review:
    summary: EEF1D alternative splicing creates heat shock transcription factor that interacts with NRF2.
    action: ACCEPT
    reason: Shows NRF2 integration with heat shock response.
    supported_by:
    - reference_id: PMID:21597468
      supporting_text: Transformation of eEF1BΞ΄ into heat-shock response transcription factor by alternative splicing.
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Transferred from mouse showing NRF2 role in UPR.
    action: ACCEPT
    reason: NRF2 is activated during UPR to maintain redox homeostasis.
- term:
    id: GO:0032993
    label: protein-DNA complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NRF2:sMAF:ARE complex transferred from mouse.
    action: ACCEPT
    reason: Core aspect of NRF2 function as ARE-binding transcription factor.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:25190803
  review:
    summary: XBP1-NRF2 interaction protects endothelial cells.
    action: ACCEPT
    reason: Core transcriptional activation function.
    supported_by:
    - reference_id: PMID:25190803
      supporting_text: Epub 2014 Sep 4. Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3.
- term:
    id: GO:0071498
    label: cellular response to fluid shear stress
  evidence_type: IDA
  original_reference_id: PMID:25190803
  review:
    summary: Shear stress activates NRF2 in endothelial cells.
    action: ACCEPT
    reason: Mechanical stress can activate NRF2 through ROS generation.
    supported_by:
    - reference_id: PMID:25190803
      supporting_text: Epub 2014 Sep 4. Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:22492997
  review:
    summary: Nuclear NRF2 detected after DJ-1-mediated stabilization.
    action: ACCEPT
    reason: Nuclear localization for transcription.
    supported_by:
    - reference_id: PMID:22492997
      supporting_text: Apr 5. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22492997
  review:
    summary: Cytoplasmic NRF2 detected in basal conditions.
    action: ACCEPT
    reason: Cytoplasmic when KEAP1-bound.
    supported_by:
    - reference_id: PMID:22492997
      supporting_text: Apr 5. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway.
- term:
    id: GO:0000976
    label: transcription cis-regulatory region binding
  evidence_type: TAS
  original_reference_id: PMID:24252804
  review:
    summary: Review on oxidative stress in Parkinson's disease noting NRF2 ARE binding.
    action: ACCEPT
    reason: Core molecular function.
    supported_by:
    - reference_id: PMID:24252804
      supporting_text: The role of oxidative stress in Parkinson's disease.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:17015834
  review:
    summary: DJ-1 stabilization of NRF2 promotes transcription of target genes.
    action: ACCEPT
    reason: Core function.
    supported_by:
    - reference_id: PMID:17015834
      supporting_text: DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2.
- term:
    id: GO:1902176
    label: negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23043106
  review:
    summary: ERK5-NRF2 pathway prevents oxidative stress-induced apoptosis in endothelium.
    action: ACCEPT
    reason: Anti-apoptotic effect is a key consequence of NRF2 antioxidant function.
    supported_by:
    - reference_id: PMID:23043106
      supporting_text: 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation.
- term:
    id: GO:2000352
    label: negative regulation of endothelial cell apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:23043106
  review:
    summary: NRF2 protects endothelial cells from apoptosis.
    action: KEEP_AS_NON_CORE
    reason: Endothelial protection is a tissue-specific effect.
    supported_by:
    - reference_id: PMID:23043106
      supporting_text: 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:18202225
  review:
    summary: Nuclear NRF2 in AML cells contributes to TNF resistance.
    action: ACCEPT
    reason: Nuclear localization for transcription.
    supported_by:
    - reference_id: PMID:18202225
      supporting_text: 2008 Jan 17. HO-1 underlies resistance of AML cells to TNF-induced apoptosis.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:18202225
  review:
    summary: NRF2 promotes HO-1 transcription in AML cells.
    action: ACCEPT
    reason: Core function.
    supported_by:
    - reference_id: PMID:18202225
      supporting_text: 2008 Jan 17. HO-1 underlies resistance of AML cells to TNF-induced apoptosis.
- term:
    id: GO:0071356
    label: cellular response to tumor necrosis factor
  evidence_type: IMP
  original_reference_id: PMID:18202225
  review:
    summary: NRF2 mediates resistance to TNF-induced apoptosis through HO-1.
    action: ACCEPT
    reason: NRF2 is activated by TNF and provides cytoprotection.
    supported_by:
    - reference_id: PMID:18202225
      supporting_text: 2008 Jan 17. HO-1 underlies resistance of AML cells to TNF-induced apoptosis.
- term:
    id: GO:0010499
    label: proteasomal ubiquitin-independent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:19424503
  review:
    summary: ENC1 promotes NRF2 degradation through ubiquitin-independent pathway.
    action: ACCEPT
    reason: Alternative NRF2 degradation mechanism.
    supported_by:
    - reference_id: PMID:19424503
      supporting_text: Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:15983046
  review:
    summary: NRF2 is subject to ubiquitination by KEAP1-CUL3 complex.
    action: ACCEPT
    reason: Core regulatory mechanism. NRF2 is a ubiquitin substrate.
    supported_by:
    - reference_id: PMID:15983046
      supporting_text: 2005 Jun 27. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway.
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:15983046
  review:
    summary: Ubiquitinated NRF2 is degraded by the proteasome.
    action: ACCEPT
    reason: Core regulatory mechanism for NRF2 turnover.
    supported_by:
    - reference_id: PMID:15983046
      supporting_text: 2005 Jun 27. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:23043106
  review:
    summary: Nuclear NRF2 detected after ERK5 activation.
    action: ACCEPT
    reason: Nuclear localization.
    supported_by:
    - reference_id: PMID:23043106
      supporting_text: 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:23043106
  review:
    summary: Cytosolic NRF2 in endothelial cells.
    action: ACCEPT
    reason: Cytosolic localization under basal conditions.
    supported_by:
    - reference_id: PMID:23043106
      supporting_text: 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation.
- term:
    id: GO:0061629
    label: RNA polymerase II-specific DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:23043106
  review:
    summary: NRF2 interacts with ERK5 transcription factor.
    action: ACCEPT
    reason: Interaction with other transcription factors for coordinate gene regulation.
    supported_by:
    - reference_id: PMID:23043106
      supporting_text: 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation.
- term:
    id: GO:0070301
    label: cellular response to hydrogen peroxide
  evidence_type: IMP
  original_reference_id: PMID:23043106
  review:
    summary: NRF2 protects endothelial cells from H2O2.
    action: ACCEPT
    reason: H2O2 is a key ROS that activates NRF2.
    supported_by:
    - reference_id: PMID:23043106
      supporting_text: 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation.
- term:
    id: GO:0071499
    label: cellular response to laminar fluid shear stress
  evidence_type: IMP
  original_reference_id: PMID:23043106
  review:
    summary: Laminar flow activates NRF2 in atheroprotection.
    action: ACCEPT
    reason: Mechanical stress activates NRF2 in vascular endothelium.
    supported_by:
    - reference_id: PMID:23043106
      supporting_text: 2012 Oct 5. Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:18554677
  review:
    summary: Metallothionein-III induces nuclear NRF2 localization.
    action: ACCEPT
    reason: Nuclear localization for transcription.
    supported_by:
    - reference_id: PMID:18554677
      supporting_text: Metallothionein-III protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a PI3K and ERK/Nrf2-dependent manner.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IDA
  original_reference_id: PMID:18554677
  review:
    summary: NRF2 DNA binding demonstrated for HO-1 promoter.
    action: ACCEPT
    reason: Core molecular function.
    supported_by:
    - reference_id: PMID:18554677
      supporting_text: Metallothionein-III protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a PI3K and ERK/Nrf2-dependent manner.
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IPI
  original_reference_id: PMID:11256947
  review:
    summary: NRF2 leucine zipper domain interacts with PMF1 coiled-coil domain.
    action: ACCEPT
    reason: Domain-specific interaction for transcriptional regulation.
    supported_by:
    - reference_id: PMID:11256947
      supporting_text: 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.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: TAS
  original_reference_id: PMID:7937919
  review:
    summary: Original cloning paper identifying NRF2 as NF-E2-like transcriptional activator.
    action: ACCEPT
    reason: Foundational evidence for NRF2 transcription factor function.
    supported_by:
    - reference_id: PMID:7937919
      supporting_text: 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.
core_functions:
- molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  description: NRF2 functions as the master transcription factor for the antioxidant response, binding to antioxidant response elements (AREs) in target gene promoters via its bZIP domain. Upon stabilization by oxidative stress or electrophile exposure, NRF2 translocates to the nucleus, heterodimerizes with small MAF proteins, and activates transcription of cytoprotective genes.
  supported_by:
  - reference_id: PMID:20452972
  - reference_id: PMID:16888629
- molecular_function:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  description: NRF2 contains a CNC-bZIP DNA-binding domain (residues 497-560) that enables sequence-specific recognition of AREs with the core sequence 5'-TGACnnnGC-3'. Structural studies demonstrate the basis for DNA recognition by NRF2-MAF heterodimers.
  supported_by:
  - reference_id: PMID:16888629
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000113
  title: Gene Ontology annotation of human sequence-specific DNA binding transcription factors (DbTFs) based on the TFClass database
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:7937919
  title: 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.
  findings:
  - statement: Original cloning and characterization of NRF2 as a bZIP transcription factor
- id: PMID:15601839
  title: BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase.
  findings:
  - statement: KEAP1 binds CUL3 via BTB domain and NRF2 via Kelch domain
  - statement: KEAP1-CUL3-ROC1 complex ubiquitinates NRF2 for proteasomal degradation
  - statement: Knocking down KEAP1 or CUL3 results in NRF2 protein accumulation
- id: PMID:16888629
  title: Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling.
  findings:
  - statement: Crystal structure of KEAP1 Kelch domain bound to NRF2 ETGE peptide at 1.5 angstrom resolution
  - statement: ETGE motif forms beta-turn structure fitting into KEAP1 binding pocket
- id: PMID:20452972
  title: p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription.
  findings:
  - statement: ARE mapped in p62 promoter responsible for NRF2-mediated induction
  - statement: ChIP and EMSA confirm NRF2 binds ARE in vivo and in vitro
  - statement: p62 competes with NRF2 for KEAP1 binding, creating positive feedback
- id: PMID:26403645
  title: Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells.
  findings:
  - statement: NRF2 protects HCC cells against ferroptosis
  - statement: NRF2 induces NQO1, HMOX1, and FTH1 to prevent ferroptosis
  - statement: NRF2 inhibition sensitizes tumors to ferroptosis-inducing agents
- id: PMID:29018201
  title: Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder.
  findings:
  - statement: Mutations in NRF2 ETGE/DLG motifs cause IMDDHH disease
  - statement: Patients have constitutive NRF2 activation with increased G6PD and GSR activity
  - statement: Demonstrates in vivo effects of chronic NRF2 hyperactivation
- id: PMID:17015834
  title: DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2.
  findings: []
- id: PMID:18048326
  title: Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha.
  findings: []
- id: PMID:18692475
  title: A protein domain-based interactome network for C. elegans early embryogenesis.
  findings: []
- id: PMID:18757741
  title: Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy.
  findings: []
- id: PMID:19706542
  title: Nitric oxide activation of Keap1/Nrf2 signaling in human colon carcinoma cells.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:23661758
  title: Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25684205
  title: CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP proteins to spatially restrict TIAM1-RAC1 signaling.
  findings: []
- id: PMID:26700459
  title: Involvement of Nrf2 in proteasome inhibition-mediated induction of ORP150 in thyroid cancer cells.
  findings: []
- id: PMID:28777872
  title: "The short isoform of PML-RARΞ± activates the NRF2/HO-1 pathway through a direct interaction with NRF2."
  findings: []
- id: PMID:29792731
  title: APR3 modulates oxidative stress and mitochondrial function in ARPE-19 cells.
  findings: []
- id: PMID:31169361
  title: A Case Study on the Keap1 Interaction with Peptide Sequence Epitopes Selected by the Peptidomic mRNA Display.
  findings: []
- id: PMID:31262713
  title: FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 binding.
  findings: []
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32911434
  title: A functionally defined high-density NRF2 interactome reveals new conditional regulators of ARE transactivation.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:34591642
  title: A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.
  findings: []
- id: PMID:35512704
  title: Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
  findings: []
- id: PMID:36442525
  title: ARD1 stabilizes NRF2 through direct interaction and promotes colon cancer progression.
  findings: []
- id: PMID:37187359
  title: Geniposide ameliorates dextran sulfate sodium-induced ulcerative colitis via KEAP1-Nrf2 signaling pathway.
  findings: []
- id: PMID:38891776
  title: Pin1 Downregulation Is Involved in Excess Retinoic Acid-Induced Failure of Neural Tube Closure.
  findings: []
- id: PMID:39009827
  title: Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.
  findings: []
- id: PMID:28566324
  title: Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals.
  findings: []
- id: PMID:36075446
  title: FOXO4 mediates resistance to oxidative stress in lens epithelial cells by modulating the TRIM25/Nrf2 signaling.
  findings: []
- id: PMID:23800989
  title: 'Nrf2 and Nrf1 signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy.'
  findings: []
- id: PMID:23043106
  title: Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation.
  findings: []
- id: PMID:24844779
  title: Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3.
  findings: []
- id: PMID:22492997
  title: DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway.
  findings: []
- id: PMID:32727915
  title: Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease.
  findings: []
- id: PMID:24366543
  title: Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1.
  findings: []
- id: PMID:34299054
  title: Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered.
  findings: []
- id: PMID:29983246
  title: The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.
  findings: []
- id: PMID:27155659
  title: Hepatitis B virus inhibits insulin receptor signaling and impairs liver regeneration via intracellular retention of the insulin receptor.
  findings: []
- id: PMID:22934019
  title: The endoplasmic reticulum stress response in aging and age-related diseases.
  findings: []
- id: PMID:22013210
  title: "The unfolded protein response: integrating stress signals through the stress sensor IRE1Ξ±."
  findings: []
- id: PMID:21597468
  title: "Transformation of eEF1BΞ΄ into heat-shock response transcription factor by alternative splicing."
  findings: []
- id: PMID:25190803
  title: Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3.
  findings: []
- id: PMID:24252804
  title: The role of oxidative stress in Parkinson's disease.
  findings: []
- id: PMID:18202225
  title: HO-1 underlies resistance of AML cells to TNF-induced apoptosis.
  findings: []
- id: PMID:19424503
  title: Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level.
  findings: []
- id: PMID:15983046
  title: Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway.
  findings: []
- id: PMID:18554677
  title: Metallothionein-III protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a PI3K and ERK/Nrf2-dependent manner.
  findings: []
- id: PMID:11256947
  title: 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.
  findings: []
- id: Reactome:R-HSA-9796067
  title: PRKAA2 phosphorylates nuclear NRF2
  findings: []
- id: Reactome:R-HSA-8932355
  title: 26S proteasome degrades ubiquitinated NRF2
  findings: []
- id: Reactome:R-HSA-9755505
  title: KEAP1:CUL3:RBX1 complex ubiquitinates NRF2
  findings: []
- id: Reactome:R-HSA-9755507
  title: VCP/p97 complex extracts ubiquitinated NRF2 for degradation
  findings: []
- id: Reactome:R-HSA-9758090
  title: Ubiquitinated NRF2 extraction from CRL3 complex
  findings: []
- id: Reactome:R-HSA-9796047
  title: PRKAA2-regulated nuclear export of NRF2
  findings: []
- id: Reactome:R-HSA-9796053
  title: PKC phosphorylates NRF2 in cytosol
  findings: []
- id: Reactome:R-HSA-8932327
  title: NRF2 binds KEAP1:NEDD8-CUL3:RBX1 in cytosol
  findings: []
- id: Reactome:R-HSA-9712274
  title: NRF2 inducers bind KEAP1:CUL3:RBX1:NRF2 in cytosol
  findings: []
- id: Reactome:R-HSA-9762100
  title: MYC and NICD1-dependent NFE2L2 gene expression
  findings: []
- id: Reactome:R-HSA-9796046
  title: NFkB-dependent NFE2L2 expression
  findings: []
- id: Reactome:R-HSA-9796060
  title: NFE2L2-dependent NFE2L2 expression (autoregulation)
  findings: []
- id: file:human/NFE2L2/NFE2L2-deep-research-falcon.md
  title: Deep research report on NFE2L2
  findings: []
tags:
- ferroptosis