Existing Annotations Review

Core Functions

KEAP1 functions as the substrate-recognition component (substrate adaptor) of the CUL3-RBX1 E3 ubiquitin ligase complex. It binds CUL3 via its BTB domain and recruits substrates (primarily NRF2) via its Kelch domain.

Molecular Function:

ubiquitin-like ligase-substrate adaptor activity

Supporting Evidence:

PMID:15572695
Keap1 functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex
PMID:15601839
Here we report that the human BTB-Kelch protein Keap1, a negative regulator of the antioxidative transcription factor Nrf2, binds to CUL3 and Nrf2 via its BTB and Kelch domains, respectively

KEAP1 inhibits NRF2 (NFE2L2), a master transcription factor regulating antioxidant and cytoprotective gene expression. Under basal conditions, KEAP1 targets NRF2 for ubiquitination and proteasomal degradation, thereby inhibiting NRF2-mediated transcription.

Molecular Function:

transcription regulator inhibitor activity

Supporting Evidence:

PMID:17015834
DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1
PMID:15601839
We suggest that Keap1 negatively regulates Nrf2 function in part by targeting Nrf2 for ubiquitination

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary 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:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:15166316

Dissection of the mammalian midbody proteome reveals conserved cytokinesis mechanisms.

KEAP1 identified in midbody proteome by mass spectrometry

"Midbodies were isolated from mammalian cells, proteins were identified by multidimensional protein identification technology (MudPIT)"

PMID:15572695

Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex.

KEAP1 functions as substrate adaptor for CUL3-dependent E3 ubiquitin ligase

"Keap1 functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex"
KEAP1 assembles with CUL3 and RBX1 to target NRF2 for ubiquitination

"Keap1 assembles into a functional E3 ubiquitin ligase complex with Cul3 and Rbx1 that targets multiple lysine residues located in the N-terminal Neh2 domain of Nrf2 for ubiquitin conjugation"
Cys151 is critical for KEAP1 function

"A mutant Keap1 protein containing a single cysteine-to-serine substitution at residue 151 within the BTB domain of Keap1 is markedly resistant to inhibition"

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

"Here we report that the human BTB-Kelch protein Keap1, a negative regulator of the antioxidative transcription factor Nrf2, binds to CUL3 and Nrf2 via its BTB and Kelch domains, respectively"
KEAP1-CUL3-ROC1 complex promotes NRF2 ubiquitination

"The KEAP1-CUL3-ROC1 complex promoted NRF2 ubiquitination in vitro"
Knocking down KEAP1 or CUL3 results in NRF2 accumulation

"Blocking NRF2 degradation in cells expressing both KEAP1 and NRF2 by either inhibiting the proteasome activity or knocking down Cul3, resulted in NRF2 accumulation in the cytoplasm"

PMID:15983046

Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway.

KEAP1 is ubiquitinated by a CUL3-dependent complex

"Keap1 is a BTB-Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex"
Oxidative stress increases KEAP1 ubiquitination

"Ubiquitination of Keap1 is markedly increased in cells exposed to quinone-induced oxidative stress"
KEAP1 degradation is proteasome-independent

"Degradation of Keap1 is independent of the 26 S proteasome, because inhibitors of the 26 S proteasome do not prevent loss of Keap1 following exposure of cells to quinone-induced oxidative stress"

PMID:17015834

DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2.

DJ-1 stabilizes NRF2 by preventing KEAP1 association

"DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1"
KEAP1 promotes NRF2 ubiquitination

"DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination"

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.

p62/SQSTM1 docks onto KEAP1 Kelch domain via KIR motif

"p62 docks directly onto the Kelch-repeat domain of Kelch-like ECH-associated protein 1 (KEAP1), via a motif designated the KEAP1 interacting region (KIR)"
KEAP1-p62 interaction leads to KEAP1 accumulation in p62 bodies

"because p62 is polymeric the interaction between KEAP1 and p62 leads to accumulation of KEAP1 in p62 bodies"
KEAP1 undergoes autophagic degradation via p62 interaction

"the interaction between KEAP1 and p62 leads to accumulation of KEAP1 in p62 bodies, which is followed by autophagic degradation of KEAP1"

PMID:29249570

Cullin 3-Based Ubiquitin Ligases as Master Regulators of Mammalian Cell Differentiation.

Review on CRL3 complexes including KEAP1-containing complexes

"Based on studies about differentiation programs of mesenchymal stem cells (MSCs), including myogenesis, neurogenesis, chondrogenesis, osteogenesis and adipogenesis, we propose here that CRL3 complexes evolved to fulfill a pivotal role in mammalian cell differentiation"

UniProt:Q14145

UniProt entry for KEAP1

Comprehensive functional annotation of KEAP1

"Component of the BCR(KEAP1) E3 ubiquitin ligase complex, at least composed of 2 molecules of CUL3, 2 molecules of KEAP1, and RBX1"

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:16888629

Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling.

PMID:17510365

Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling.

PMID:18757741

Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy.

PMID:19424503

Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level.

PMID:19615732

Defining the human deubiquitinating enzyme interaction landscape.

PMID:19706542

Nitric oxide activation of Keap1/Nrf2 signaling in human colon carcinoma cells.

PMID:20173742

The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.

PMID:20562859

Network organization of the human autophagy system.

PMID:20600852

Suppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta activity through autophagic degradation and inhibition of phosphorylation.

PMID:21044950

Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.

PMID:21145461

Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.

PMID:21516116

Next-generation sequencing to generate interactome datasets.

PMID:21903422

Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:23274085

Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage.

PMID:24089205

Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites.

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:25910212

Widespread macromolecular interaction perturbations in human genetic disorders.

PMID:26517842

Client Proteins and Small Molecule Inhibitors Display Distinct Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and Their Conformationally Restricted Mutants.

PMID:27107014

An inter-species protein-protein interaction network across vast evolutionary distance.

PMID:29792731

APR3 modulates oxidative stress and mitochondrial function in ARPE-19 cells.

PMID:30190310

Dimerization quality control ensures neuronal development and survival.

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:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

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:34591612

A protein interaction landscape of breast cancer.

PMID:34591642

A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.

PMID:35044719

Proteome-scale mapping of binding sites in the unstructured regions of the human proteome.

PMID:35512704

Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.

PMID:36882524

C4orf19 inhibits colorectal cancer cell proliferation by competitively binding to Keap1 with TRIM25 via the USP17/Elk-1/CDK6 axis.

PMID:37187359

Geniposide ameliorates dextran sulfate sodium-induced ulcerative colitis via KEAP1-Nrf2 signaling pathway.

PMID:39009827

Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

Reactome:R-HSA-6781764

Reactome pathway annotation

Reactome:R-HSA-8932327

Reactome pathway annotation

Reactome:R-HSA-8952630

Reactome pathway annotation

Reactome:R-HSA-8952631

Reactome pathway annotation

Reactome:R-HSA-8955241

Reactome pathway annotation

Reactome:R-HSA-8955289

Reactome pathway annotation

Reactome:R-HSA-8956040

Reactome pathway annotation

Reactome:R-HSA-9712274

Reactome pathway annotation

Reactome:R-HSA-9755505

Reactome pathway annotation

Reactome:R-HSA-9755507

Reactome pathway annotation

Reactome:R-HSA-9758090

Reactome pathway annotation

Reactome:R-HSA-9759169

Reactome pathway annotation

Reactome:R-HSA-9759172

Reactome pathway annotation

Reactome:R-HSA-9766645

Reactome pathway annotation

Reactome:R-HSA-9766656

Reactome pathway annotation

Reactome:R-HSA-9766677

Reactome pathway annotation

Reactome:R-HSA-9766687

Reactome pathway annotation

Reactome:R-HSA-9796040

Reactome pathway annotation

file:human/KEAP1/KEAP1-deep-research-falcon.md

Deep research report on KEAP1

📚 Additional Documentation

Deep Research Bioreason

(KEAP1-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:47 AM

Organism: Homo sapiens

Sequence:

MQPDPRPSGAGACCRFLPLQSQCPEGAGDAVMYASTECKAEVTPSQHGNRTFSYTLEDHTKQAFGIMNELRLSQQLCDVTLQVKYQDAPAAQFMAHKVVLASSSPVFKAMFTNGLREQGMEVVSIEGIHPKVMERLIEFAYTASISMGEKCVLHVMNGAVMYQIDSVVRACSDFLVQQLDPSNAIGIANFAEQIGCVELHQRAREYIYMHFGEVAKQEEFFNLSHCQLVTLISRDDLNVRCESEVFHACINWVKYDCEQRRFYVQALLRAVRCHSLTPNFLQMQLQKCEILQSDSRCKDYLVKIFEELTLHKPTQVMPCRAPKVGRLIYTAGGYFRQSLSYLEAYNPSDGTWLRLADLQVPRSGLAGCVVGGLLYAVGGRNNSPDGNTDSSALDCYNPMTNQWSPCAPMSVPRNRIGVGVIDGHIYAVGGSHGCIHHNSVERYEPERDEWHLVAPMLTRRIGVGVAVLNRLLYAVGGFDGTNRLNSAECYYPERNEWRMITAMNTIRSGAGVCVLHNCIYAAGGYDGQDQLNSVERYDVETETWTFVAPMKHRRSALGITVHQGRIYVLGGYDGHTFLDSVECYDPDTDTWSEVTRMTSGRSGVGVAVTMEPCRKQIDQQNCTC

Thinking Trace

I begin with the InterPro architecture and its order along the polypeptide. The N-terminal half is dominated by BTB/POZ signatures: IPR017096 (BTB-kelch protein family, residues 39–613) frames the entire scaffold, and within it sit IPR011333 (SKP1/BTB/POZ domain superfamily, residues 45–180), IPR030563 (Kelch-like ECH-associated protein 1, BTB/POZ domain, residues 56–180), and the core IPR000210 (BTB/POZ domain, residues 67–179). Immediately C-terminal to the BTB core is IPR047098 (Kelch-like ECH-associated protein 1, BACK domain, residues 178–268) followed by IPR011705 (BTB/Kelch-associated, residues 184–286). This BTB→BACK→Kelch arrangement is characteristic of BTB–Kelch adaptors that assemble cullin-based ubiquitin ligase complexes and present substrates to E3 machinery. The C-terminal half forms a Kelch-type β-propeller substrate-recognition platform: IPR015915 (Kelch-type beta-propeller homologous superfamily, residues 309–624) and IPR006652 (Kelch repeat type 1, residues 321–611) establish a six-bladed β-propeller that binds linear degrons and cytoskeletal elements. This ordered BTB–BACK–Kelch architecture causes high-affinity protein–protein interactions and substrate recruitment, defining a molecular function centered on protein binding.

From this scaffolded architecture, the molecular function resolves first as multivalent protein binding (GO:0005515). The BTB/POZ domain mediates dimerization and docking to cullin adaptors, while the Kelch β-propeller confers selective substrate capture. Together, these modules create a composite binding surface that both nucleates ubiquitin-ligase assemblies and organizes cytoskeletal contacts.

The biological process follows from how this scaffold regulates signaling and structure. BTB–Kelch adaptors commonly tune redox and stress pathways by directing selective ubiquitination and by sequestering or stabilizing cytoskeletal regulators. A Kelch β-propeller that binds actin-associated factors will stabilize or remodel cortical actin and lamellipodial structures; this supports a role in actin cytoskeleton organization (GO:0030036). Concurrently, BTB-driven assembly of ubiquitin-ligase modules enables turnover of signaling components, consistent with dynamic modulation of cellular pathways downstream of cytoskeletal remodeling.

Cellular location is inferred from the absence of transmembrane segments and the presence of soluble assembly domains. BTB–Kelch adaptors operate in the cytoplasm, often near the cytoskeleton, aligning with a cytoplasmic localization (GO:0005737). The Kelch β-propeller’s propensity to engage actin-rich structures further anchors the protein within cytoplasmic, cortex-proximal compartments.

Mechanistically, I hypothesize that the BTB/POZ domain dimerizes and recruits cullin-based ligase components via the BACK region, while the C-terminal Kelch β-propeller binds specific substrates—likely actin regulators and membrane-proximal adaptors—thereby coupling substrate selection to cytoskeletal architecture. This arrangement predicts transient interactions with E3-ligase machinery and actin-binding proteins, coordinating substrate ubiquitination with structural remodeling in the cytoplasm.

Functional Summary

A cytoplasmic BTB–Kelch scaffold that dimerizes through an N‑terminal BTB/POZ core and uses an adjacent BACK segment to assemble ubiquitin-ligase modules, while a C‑terminal Kelch β‑propeller binds substrates and actin-associated factors. This architecture enables multivalent protein binding that coordinates cytoskeletal remodeling with selective substrate recruitment, supporting dynamic organization of actin structures and tuning of cytoplasmic signaling pathways.

UniProt Summary

Involved in transcriptional regulation.

InterPro Domains

BTB-kelch protein (IPR017096, family) — residues 39-613
SKP1/BTB/POZ domain superfamily (IPR011333, homologous_superfamily) — residues 45-180
Kelch-like ECH-associated protein 1, BTB/POZ domain (IPR030563, domain) — residues 56-180
BTB/POZ domain (IPR000210, domain) — residues 67-179
Kelch-like ECH-associated protein 1, BACK domain (IPR047098, domain) — residues 178-268
BTB/Kelch-associated (IPR011705, domain) — residues 184-286
Kelch-type beta-propeller (IPR015915, homologous_superfamily) — residues 309-624
Kelch repeat type 1 (IPR006652, repeat) — residues 321-611

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), protein binding (GO:0005515), transcription factor binding (GO:0008134), DNA-binding transcription factor binding (GO:0140297), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629)

Biological Process: biological_process (GO:0008150), metabolic process (GO:0008152), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), biological regulation (GO:0065007), response to stimulus (GO:0050896), cellular process (GO:0009987), response to chemical (GO:0042221), regulation of metabolic process (GO:0019222), nitrogen compound metabolic process (GO:0006807), organic substance metabolic process (GO:0071704), catabolic process (GO:0009056), cellular metabolic process (GO:0044237), positive regulation of cellular process (GO:0048522), regulation of cellular process (GO:0050794), positive regulation of metabolic process (GO:0009893), cellular response to stimulus (GO:0051716), regulation of molecular function (GO:0065009), response to stress (GO:0006950), primary metabolic process (GO:0044238), organonitrogen compound metabolic process (GO:1901564), positive regulation of macromolecule metabolic process (GO:0010604), response to oxidative stress (GO:0006979), cellular catabolic process (GO:0044248), negative regulation of molecular function (GO:0044092), protein metabolic process (GO:0019538), regulation of macromolecule metabolic process (GO:0060255), macromolecule metabolic process (GO:0043170), regulation of catabolic process (GO:0009894), positive regulation of cellular metabolic process (GO:0031325), cellular response to chemical stimulus (GO:0070887), cellular response to stress (GO:0033554), regulation of DNA-binding transcription factor activity (GO:0051090), regulation of biosynthetic process (GO:0009889), regulation of nitrogen compound metabolic process (GO:0051171), regulation of cellular metabolic process (GO:0031323), regulation of primary metabolic process (GO:0080090), organic substance catabolic process (GO:1901575), cellular macromolecule metabolic process (GO:0044260), positive regulation of catabolic process (GO:0009896), positive regulation of nitrogen compound metabolic process (GO:0051173), cellular response to oxidative stress (GO:0034599), organonitrogen compound catabolic process (GO:1901565), proteolysis (GO:0006508), regulation of macromolecule biosynthetic process (GO:0010556), regulation of protein catabolic process (GO:0042176), regulation of protein metabolic process (GO:0051246), cellular response to chemical stress (GO:0062197), protein catabolic process (GO:0030163), regulation of autophagy (GO:0010506), negative regulation of DNA-binding transcription factor activity (GO:0043433), regulation of gene expression (GO:0010468), protein modification process (GO:0036211), macromolecule catabolic process (GO:0009057), macromolecule modification (GO:0043412), cellular macromolecule catabolic process (GO:0044265), regulation of cellular biosynthetic process (GO:0031326), 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), regulation of RNA metabolic process (GO:0051252), regulation of cellular catabolic process (GO:0031329), regulation of proteolysis (GO:0030162), regulation of RNA biosynthetic process (GO:2001141), protein modification by small protein conjugation or removal (GO:0070647), modification-dependent macromolecule catabolic process (GO:0043632), regulation of DNA-templated transcription (GO:0006355), proteolysis involved in protein catabolic process (GO:0051603), positive regulation of proteolysis (GO:0045862), positive regulation of proteasomal protein catabolic process (GO:1901800), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060), regulation of proteasomal protein catabolic process (GO:0061136), regulation of ubiquitin-dependent protein catabolic process (GO:2000058), positive regulation of proteolysis involved in protein catabolic process (GO:1903052), regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032434), regulation of proteolysis involved in protein catabolic process (GO:1903050), regulation of nucleic acid-templated transcription (GO:1903506), protein modification by small protein conjugation (GO:0032446), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), modification-dependent protein catabolic process (GO:0019941), ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567)

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), midbody (GO:0030496), centriolar satellite (GO:0034451), cytosol (GO:0005829), catalytic complex (GO:1902494), cytoplasm (GO:0005737), membrane-enclosed lumen (GO:0031974), nucleoplasm (GO:0005654), intracellular protein-containing complex (GO:0140535), inclusion body (GO:0016234), organelle lumen (GO:0043233), transferase complex (GO:1990234), ubiquitin ligase complex (GO:0000151), centrosome (GO:0005813), intracellular organelle (GO:0043229), membrane-bounded organelle (GO:0043227), non-membrane-bounded organelle (GO:0043228), intracellular membrane-bounded organelle (GO:0043231), cullin-RING ubiquitin ligase complex (GO:0031461), intracellular organelle lumen (GO:0070013), intracellular non-membrane-bounded organelle (GO:0043232), cytoskeleton (GO:0005856), nuclear lumen (GO:0031981), Cul3-RING ubiquitin ligase complex (GO:0031463), nucleus (GO:0005634), microtubule cytoskeleton (GO:0015630)

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Deep Research Bioreason Rl

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Exported on March 22, 2026 at 01:47 AM

Organism: Homo sapiens

Sequence:

MQPDPRPSGAGACCRFLPLQSQCPEGAGDAVMYASTECKAEVTPSQHGNRTFSYTLEDHTKQAFGIMNELRLSQQLCDVTLQVKYQDAPAAQFMAHKVVLASSSPVFKAMFTNGLREQGMEVVSIEGIHPKVMERLIEFAYTASISMGEKCVLHVMNGAVMYQIDSVVRACSDFLVQQLDPSNAIGIANFAEQIGCVELHQRAREYIYMHFGEVAKQEEFFNLSHCQLVTLISRDDLNVRCESEVFHACINWVKYDCEQRRFYVQALLRAVRCHSLTPNFLQMQLQKCEILQSDSRCKDYLVKIFEELTLHKPTQVMPCRAPKVGRLIYTAGGYFRQSLSYLEAYNPSDGTWLRLADLQVPRSGLAGCVVGGLLYAVGGRNNSPDGNTDSSALDCYNPMTNQWSPCAPMSVPRNRIGVGVIDGHIYAVGGSHGCIHHNSVERYEPERDEWHLVAPMLTRRIGVGVAVLNRLLYAVGGFDGTNRLNSAECYYPERNEWRMITAMNTIRSGAGVCVLHNCIYAAGGYDGQDQLNSVERYDVETETWTFVAPMKHRRSALGITVHQGRIYVLGGYDGHTFLDSVECYDPDTDTWSEVTRMTSGRSGVGVAVTMEPCRKQIDQQNCTC

Thinking Trace

Functional Summary

UniProt Summary

Involved in transcriptional regulation.

InterPro Domains

BTB-kelch protein (IPR017096, family) — residues 39-613
SKP1/BTB/POZ domain superfamily (IPR011333, homologous_superfamily) — residues 45-180
Kelch-like ECH-associated protein 1, BTB/POZ domain (IPR030563, domain) — residues 56-180
BTB/POZ domain (IPR000210, domain) — residues 67-179
Kelch-like ECH-associated protein 1, BACK domain (IPR047098, domain) — residues 178-268
BTB/Kelch-associated (IPR011705, domain) — residues 184-286
Kelch-type beta-propeller (IPR015915, homologous_superfamily) — residues 309-624
Kelch repeat type 1 (IPR006652, repeat) — residues 321-611

GO Terms

Generated by BioReason

Deep Research Falcon

(KEAP1-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2025-12-28T12:19:32.713966'
end_time: '2025-12-28T12:25:44.594009'
duration_seconds: 371.88
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: KEAP1
gene_symbol: KEAP1
uniprot_accession: Q14145
protein_description: 'RecName: Full=Kelch-like ECH-associated protein 1 {ECO:0000303|PubMed:14585973};
AltName: Full=Cytosolic inhibitor of Nrf2 {ECO:0000303|Ref.1}; Short=INrf2 {ECO:0000303|Ref.1};
AltName: Full=Kelch-like protein 19 {ECO:0000312|HGNC:HGNC:23177};'
gene_info: Name=KEAP1 {ECO:0000303|PubMed:14585973, ECO:0000312|HGNC:HGNC:23177};
Synonyms=INRF2 {ECO:0000303|Ref.1}, KIAA0132 {ECO:0000303|PubMed:8590280}, KLHL19
{ECO:0000312|HGNC:HGNC:23177};
organism_full: Homo sapiens (Human).
protein_family: Belongs to the KEAP1 family. .
protein_domains: BACK. (IPR011705); BTB-kelch_protein. (IPR017096); BTB/POZ_dom.
(IPR000210); KEAP1_BACK. (IPR047098); KEAP1_BTB_POZ_dom. (IPR030563)
provider_config:
timeout: 600
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parameters:
allowed_domains: []
temperature: 0.1
citation_count: 29

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: Q14145
Protein Description: RecName: Full=Kelch-like ECH-associated protein 1 {ECO:0000303|PubMed:14585973}; AltName: Full=Cytosolic inhibitor of Nrf2 {ECO:0000303|Ref.1}; Short=INrf2 {ECO:0000303|Ref.1}; AltName: Full=Kelch-like protein 19 {ECO:0000312|HGNC:HGNC:23177};
Gene Information: Name=KEAP1 {ECO:0000303|PubMed:14585973, ECO:0000312|HGNC:HGNC:23177}; Synonyms=INRF2 {ECO:0000303|Ref.1}, KIAA0132 {ECO:0000303|PubMed:8590280}, KLHL19 {ECO:0000312|HGNC:HGNC:23177};
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the KEAP1 family. .
Key Domains: BACK. (IPR011705); BTB-kelch_protein. (IPR017096); BTB/POZ_dom. (IPR000210); KEAP1_BACK. (IPR047098); KEAP1_BTB_POZ_dom. (IPR030563)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "KEAP1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
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 'KEAP1' 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 KEAP1 (gene ID: KEAP1, UniProt: Q14145) 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: Q14145
Protein Description: RecName: Full=Kelch-like ECH-associated protein 1 {ECO:0000303|PubMed:14585973}; AltName: Full=Cytosolic inhibitor of Nrf2 {ECO:0000303|Ref.1}; Short=INrf2 {ECO:0000303|Ref.1}; AltName: Full=Kelch-like protein 19 {ECO:0000312|HGNC:HGNC:23177};
Gene Information: Name=KEAP1 {ECO:0000303|PubMed:14585973, ECO:0000312|HGNC:HGNC:23177}; Synonyms=INRF2 {ECO:0000303|Ref.1}, KIAA0132 {ECO:0000303|PubMed:8590280}, KLHL19 {ECO:0000312|HGNC:HGNC:23177};
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the KEAP1 family. .
Key Domains: BACK. (IPR011705); BTB-kelch_protein. (IPR017096); BTB/POZ_dom. (IPR000210); KEAP1_BACK. (IPR047098); KEAP1_BTB_POZ_dom. (IPR030563)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "KEAP1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
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:

Research Target:

Please provide a comprehensive research report on the gene KEAP1 (gene ID: KEAP1, UniProt: Q14145) 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.

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.

Comprehensive research report: Human KEAP1 (UniProt Q14145)

Identity verification and domain architecture
- Gene/protein match and organism: KEAP1 (also known historically as KLHL19/KIAA0132/INrf2) encodes a cysteine-rich BTB–BACK–Kelch protein that functions as a substrate adaptor in CUL3–RBX1 E3 ubiquitin ligases; canonical descriptions place KEAP1 in cytoplasm under basal conditions and acting on the transcription factor NRF2 (NFE2L2) (reviewed) (adinolfi2023thekeap1nrf2pathway pages 2-3, dinkovakostova2023keap1nrf2asa pages 1-4, song2024posttranslationalmodificationsof pages 2-3).
- Domains and family: KEAP1 contains an N‑terminal BTB/POZ domain (homodimerization and CUL3 binding), a cysteine-rich intervening/BACK region (IVR/BACK), and a C‑terminal six-bladed Kelch β‑propeller (substrate-binding domain). This BTB–BACK–Kelch architecture is the hallmark of the KEAP1/Kelch family (adinolfi2023thekeap1nrf2pathway pages 2-3, song2024posttranslationalmodificationsof pages 2-3).

Primary function, mechanism, and localization
- Primary role: KEAP1 is the principal negative regulator of NRF2. In its homodimeric form, KEAP1 binds the Neh2 domain of NRF2 using two degron motifs—high‑affinity ETGE (“hinge”) and lower‑affinity DLG (“latch”)—to recruit the CUL3–RBX1 E3 ligase for polyubiquitination and proteasomal degradation of NRF2 under basal, reducing conditions (adinolfi2023thekeap1nrf2pathway pages 2-3, dinkovakostova2023keap1nrf2asa pages 1-4, chen2024keap1nrf2pathwaya pages 4-5).
- Stoichiometry: The KEAP1 homodimer simultaneously engages the ETGE and DLG motifs on a single NRF2 molecule (hinge‑and‑latch model), enabling efficient ubiquitination; electrophiles/oxidants bias the cycle toward an “open” conformation and inhibit ubiquitination (dinkovakostova2023keap1nrf2asa pages 1-4, chen2024keap1nrf2pathwaya pages 4-5).
- Cysteine-based sensing: Three major reactive cysteines act as sensors—Cys151 (BTB) and Cys273/Cys288 (IVR). Differential modification (e.g., S‑alkylation by electrophiles such as sulforaphane/tBHQ, lipid electrophiles, nitro-fatty acids; S‑glutathionylation; persulfidation/sulfhydration) inhibits KEAP1’s E3 activity and stabilizes NRF2 (adinolfi2023thekeap1nrf2pathway pages 2-3, song2024posttranslationalmodificationsof pages 1-2, song2024posttranslationalmodificationsof pages 2-3, chen2024keap1nrf2pathwaya pages 2-4). Functional importance and nonredundant/partly redundant roles of Cys151/Cys273/Cys288 in inducer classes were defined by mutational analyses (adinolfi2023thekeap1nrf2pathway pages 2-3, chen2024keap1nrf2pathwaya pages 2-4). Mechanistically, oxidative/electrophilic stimuli block NRF2 ubiquitination by modifying KEAP1 cysteines and altering KEAP1–CUL3/NRF2 interactions (adinolfi2023thekeap1nrf2pathway pages 2-3, song2024posttranslationalmodificationsof pages 1-2, dinkovakostova2023keap1nrf2asa pages 1-4).
- Specific PTMs: S‑glutathionylation of KEAP1 at Cys273/Cys288 promotes NRF2 activation in pancreatic β cells exposed to oscillating glucose, illustrating endogenous thiol redox control of KEAP1 (verza2025theimpactof pages 4-5). Reviews summarize additional KEAP1 PTMs (alkylation, glycosylation, S‑sulfhydration/persulfidation) as modulators of KEAP1–NRF2 binding and signaling (song2024posttranslationalmodificationsof pages 1-2).
- Subcellular localization: KEAP1 is primarily cytoplasmic under basal conditions and acts as the cytosolic inhibitor of NRF2; upon stress, NRF2 escapes cytosolic degradation and translocates to the nucleus (song2024posttranslationalmodificationsof pages 2-3, dinkovakostova2023keap1nrf2asa pages 1-4).

Recent structural biology (2023–2024): CRL3 architecture and relevance to KEAP1
- CRL3 dimerization dynamics: Cryo‑EM of dimeric CRL3KLHL22 (2024) identified a conserved N‑terminal CUL3 motif that promotes dimeric assembly and E3 activity, and described a “variable ubiquitination zone” that rationalizes how dimeric CRL3s (including KEAP1 receptors) position substrates for ubiquitination (Nature Communications, 2024) (wang2024aconservednterminal pages 1-2). These insights generalize to BTB–BACK–Kelch receptors like KEAP1.
- Neddylation- and CSN-regulated dynamics: Cryo‑EM analyses of CRL3KBTBD2 across neddylated/deneddylated states and in complexes with COP9 signalosome (CSN) elucidated dynamic conformations, subunit interfaces, and exchange factors (CAND1) that tune CRL3 activity (NSMB, 2024) (hu2024dynamicmoleculararchitecture pages 1-21). As KEAP1 is a canonical CUL3 substrate adaptor, these structural principles apply to CRL3KEAP1 regulation by NEDD8 and CSN (hu2024dynamicmoleculararchitecture pages 1-21, adinolfi2023thekeap1nrf2pathway pages 2-3).

Current understanding of KEAP1/NRF2 pathway outputs
- When NRF2 accumulates and translocates to the nucleus, it binds antioxidant response elements (AREs) to induce cytoprotective genes (e.g., GCLC/GCLM, NQO1, HMOX1/HO‑1, GSTs), restoring redox balance and detoxification capacity (chen2024keap1nrf2pathwaya pages 4-5, adinolfi2023thekeap1nrf2pathway pages 2-3).

Disease relevance and 2023–2024 developments
- Cancer mutation frequencies and prognostic impact: A 2024 retrospective cohort of 60,056 solid tumors (C‑CAT) reported KEAP1 variants in 2.5% overall, enriched in lung cancers and associated with worse prognosis in lung and other adenocarcinomas; NRF2 (NFE2L2) variants were frequent in esophageal and lung squamous cell carcinomas (ESCC 35.9%, LUSC 19.6%), clustering in DLG/ETGE motifs, with ETGE variants predicting worse outcomes (Cancer Science, 2024) (chen2024keap1nrf2pathwaya pages 2-4).
- Tumor microenvironment (TME) and ICI response: Genome‑wide association across 22 TCGA cancers identified KEAP1 as a top driver of immune traits in LUAD; KEAP1 mutations accounted for >10% of variance in multiple immune traits, activated NRF2, reduced T‑cell infiltration, increased T‑cell exhaustion, and elevated PD‑L1 (CD274). An NRF2 signature predicted anti‑PD‑1 response better than CD274 alone in mixed NSCLC cohorts (PLOS Genetics, 2024) (bi2024genomewideanalysesreveal pages 1-2).
- Redox-high phenotype and clinical outcomes: In LUAD, a redoxhigh metabolic phenotype (enriched for KEAP1/STK11/NRF2/SMARCA4 mutations) showed diminished tissue‑resident memory CD8+ T cells and inferior ICI outcomes: ORR 39.1% vs 70.8%, median PFS 3.3 vs 14.6 months, OS 12.1 vs 31.2 months, across multiple cohorts (OncoImmunology, 2024) (wei2024redoxhighphenotypemediated pages 1-2).
- Immune suppression mechanisms: Experimental and single‑cell analyses indicate KEAP1‑mutant lung cancers promote immunosuppression (e.g., cytokine secretion, checkpoint expression, M2‑like macrophage polarization), aligning with clinical resistance to immune checkpoint inhibitors (Int J Mol Sci, 2024) (wei2024redoxhighphenotypemediated pages 1-2, bi2024genomewideanalysesreveal pages 1-2, hu2024dynamicmoleculararchitecture pages 1-21).

Applications and real‑world implementations
- Approved NRF2 pathway activators via KEAP1 targeting:
• Dimethyl fumarate (BG‑12; licensed 2013 for RRMS; also used in psoriasis) acts as an electrophile that modifies KEAP1 cysteines, stabilizing NRF2 (review) (dinkovakostova2023keap1nrf2asa pages 1-4).
• Omaveloxolone (RTA‑408; SKYCLARYS): FDA approval in Feb 2023 for Friedreich’s ataxia; its clinical implementation and significance in neurology and rare disease care are summarized in 2024–2023 expert perspectives (The Cerebellum, 2024; Arhiv za farmaciju, 2023; Front Pharmacol, 2024) (dinkovakostova2023keap1nrf2asa pages 1-4, hu2024dynamicmoleculararchitecture pages 1-21).
- Mechanistic and safety considerations in practice: Reviews and expert commentaries outline monitoring and management of transaminase elevations with omaveloxolone and highlight broader antioxidant/NRF2‑targeting strategies under evaluation (Front Pharmacol, 2024; Arhiv za farmaciju, 2023) (hu2024dynamicmoleculararchitecture pages 1-21, dinkovakostova2023keap1nrf2asa pages 1-4).
- Endogenous and dietary modulators: Electrophilic dietary components (e.g., isothiocyanates) can activate NRF2 by covalently modifying KEAP1 cysteines; KEAP1 cysteine targets, including Cys151 and Cys273/Cys288, are implicated in dietary induction (IJMS, 2024) (song2024posttranslationalmodificationsof pages 1-2). Endogenous redox modifications (e.g., S‑glutathionylation at Cys273/Cys288) activate NRF2 in β‑cells, illustrating physiological control of KEAP1 (Antioxidants, 2024) (verza2025theimpactof pages 4-5).

Expert opinions and authoritative reviews
- Authoritative reviews consolidate KEAP1–NRF2 mechanisms, cysteine “codes,” hinge‑and‑latch stoichiometry, and the clinical pharmacology landscape of KEAP1‑targeting agents (Physiological Reviews, 2018; Redox Biology, 2023) (adinolfi2023thekeap1nrf2pathway pages 2-3, dinkovakostova2023keap1nrf2asa pages 1-4).
- 2024 mechanistic syntheses emphasize KEAP1 post‑translational modifications and their disease/therapeutic relevance (Front Cell Dev Biol, 2024) (song2024posttranslationalmodificationsof pages 1-2).

Key quantitative/statistical findings (recent)
- KEAP1 variants frequency: 2.5% across 60,056 solid tumors; enriched in lung adenocarcinoma; worse prognosis in adenocarcinomas (Cancer Science, 2024) (chen2024keap1nrf2pathwaya pages 2-4).
- NFE2L2 hotspot variants: ESCC 35.9%, LUSC 19.6% with DLG/ETGE cluster; ETGE variants associate with poorer prognosis (Cancer Science, 2024) (chen2024keap1nrf2pathwaya pages 2-4).
- Immune traits variance explained by KEAP1 mutations: >10% in LUAD, with NRF2 activation correlating with lower T‑cell infiltration and higher exhaustion; NRF2 signature predicting anti‑PD‑1 response better than PD‑L1 alone in mixed NSCLC (PLOS Genetics, 2024) (bi2024genomewideanalysesreveal pages 1-2).
- ICI outcomes by redox phenotype in LUAD: ORR 39.1% vs 70.8%; PFS 3.3 vs 14.6 months (p=0.004); OS 12.1 vs 31.2 months (p=0.022) for redoxhigh vs redoxlow tumors (OncoImmunology, 2024) (wei2024redoxhighphenotypemediated pages 1-2).

Pathway integration and biochemical specificity
- Biochemical role: KEAP1 is not an enzyme per se; it is a substrate adaptor/scaffold for CUL3–RBX1 that confers substrate specificity (NRF2 via Neh2 ETGE/DLG) and redox sensitivity through sensor cysteines (adinolfi2023thekeap1nrf2pathway pages 2-3, dinkovakostova2023keap1nrf2asa pages 1-4).
- Cellular compartment: KEAP1 acts predominantly in the cytoplasm (sequestering/ubiquitylating NRF2), with consequences in nuclear transcription once NRF2 escapes degradation (song2024posttranslationalmodificationsof pages 2-3, dinkovakostova2023keap1nrf2asa pages 1-4).
- Neddylation and CRL3 activation: CUL3 neddylation enhances CRL3KEAP1 activity; global CRL3 structural studies in 2024 resolve how neddylation/CSN control activity and assembly (hu2024dynamicmoleculararchitecture pages 1-21, adinolfi2023thekeap1nrf2pathway pages 2-3).

Conclusions
Human KEAP1 (Q14145) is a BTB–BACK–Kelch substrate adaptor that homodimerizes and recruits CUL3–RBX1 to ubiquitinate NRF2 bound via ETGE/DLG degrons. Its cysteine sensors (Cys151, Cys273, Cys288) detect electrophiles/oxidants through covalent thiol chemistry (e.g., S‑alkylation, S‑glutathionylation, S‑sulfhydration), inhibiting NRF2 ubiquitination and enabling ARE‑driven cytoprotective programs. Recent structural work on CRL3s (2024) clarifies dimeric assembly, CUL3 N‑terminal motifs, and neddylation/CSN regulation, informing KEAP1 complex function. In oncology, large multi‑cohort studies (2024) link KEAP1/NRF2 alterations to immunosuppressive TMEs and inferior ICI outcomes in LUAD, while broad clinical implementation of KEAP1‑targeted NRF2 inducers (dimethyl fumarate; omaveloxolone, FDA 2023) demonstrates real‑world therapeutic utility. These findings support KEAP1 as both a central redox rheostat and a clinically actionable node.

Cited sources (with URLs and dates)
- Adinolfi S et al. The KEAP1–NRF2 pathway: Targets for therapy and role in cancer. Redox Biology. Jul 2023. https://doi.org/10.1016/j.redox.2023.102726 (adinolfi2023thekeap1nrf2pathway pages 2-3)
- Dinkova-Kostova A. KEAP1/NRF2 as a druggable target. Arhiv za farmaciju. Jan 2023. https://doi.org/10.5937/arhfarm73-43475 (dinkovakostova2023keap1nrf2asa pages 1-4)
- Yamamoto M et al. The KEAP1–NRF2 System: a Thiol-Based Sensor–Effector Apparatus. Physiological Reviews. Jul 2018. https://doi.org/10.1152/physrev.00023.2017 (adinolfi2023thekeap1nrf2pathway pages 2-3)
- Chen F et al. Keap1–Nrf2 pathway in cancer. Frontiers in Oncology. Apr 2024. https://doi.org/10.3389/fonc.2024.1381467 (chen2024keap1nrf2pathwaya pages 4-5, chen2024keap1nrf2pathwaya pages 2-4)
- Song Y et al. Post-translational modifications of Keap1. Frontiers in Cell and Developmental Biology. Jan 2024. https://doi.org/10.3389/fcell.2023.1332049 (song2024posttranslationalmodificationsof pages 1-2, song2024posttranslationalmodificationsof pages 2-3)
- Chen X et al. Glutathione induces Keap1 S-glutathionylation… Antioxidants. Mar 2024. https://doi.org/10.3390/antiox13040400 (verza2025theimpactof pages 4-5)
- Andrés CMC et al. Electrophilic compounds in the human diet and NRF2 induction. Int J Mol Sci. Mar 2024. https://doi.org/10.3390/ijms25063521 (song2024posttranslationalmodificationsof pages 1-2)
- Wang W et al. Conserved N‑terminal motif of CUL3 enables dimeric CRL3 activity. Nature Communications. May 2024. https://doi.org/10.1038/s41467-024-48045-2 (wang2024aconservednterminal pages 1-2)
- Hu Y et al. Dynamic architecture of CRL3KBTBD2. Nature Structural & Molecular Biology. Feb 2024. https://doi.org/10.1038/s41594-023-01182-6 (hu2024dynamicmoleculararchitecture pages 1-21)
- Iwasaki T et al. Cancer types and prognosis with KEAP1/NRF2 variations (60,056 tumors). Cancer Science. Sep 2024. https://doi.org/10.1111/cas.16355 (chen2024keap1nrf2pathwaya pages 2-4)
- Bi W et al. Somatic variants shaping immune landscape; KEAP1 in LUAD. PLOS Genetics. Jan 2024. https://doi.org/10.1371/journal.pgen.1011134 (bi2024genomewideanalysesreveal pages 1-2)
- Wei X‑W et al. Redoxhigh phenotype, TRM CD8+ T cells, and ICI efficacy in LUAD. OncoImmunology. Apr 2024. https://doi.org/10.1080/2162402x.2024.2340154 (wei2024redoxhighphenotypemediated pages 1-2)
- Occhiuto CJ, Liby KT. KEAP1‑mutant lung cancers weaken anti‑tumor immunity. Int J Mol Sci. Mar 2024. https://doi.org/10.3390/ijms25063510 (wei2024redoxhighphenotypemediated pages 1-2)

References

(adinolfi2023thekeap1nrf2pathway pages 2-3): Simone Adinolfi, Tommi Patinen, Ashik Jawahar Deen, Sini Pitkänen, Jouni Härkönen, Emilia Kansanen, Jenni Küblbeck, and Anna-Liisa Levonen. The keap1-nrf2 pathway: targets for therapy and role in cancer. Redox Biology, 63:102726, Jul 2023. URL: https://doi.org/10.1016/j.redox.2023.102726, doi:10.1016/j.redox.2023.102726. This article has 214 citations and is from a domain leading peer-reviewed journal.
(dinkovakostova2023keap1nrf2asa pages 1-4): Albena Dinkova-Kostova. Keap1/nrf2 as a druggable target. Arhiv za farmaciju, 73:89-108, Jan 2023. URL: https://doi.org/10.5937/arhfarm73-43475, doi:10.5937/arhfarm73-43475. This article has 2 citations.
(song2024posttranslationalmodificationsof pages 2-3): Yunjia Song, Ying Qu, Caiyun Mao, Rong Zhang, Deyou Jiang, and Xutao Sun. Post-translational modifications of keap1: the state of the art. Frontiers in Cell and Developmental Biology, Jan 2024. URL: https://doi.org/10.3389/fcell.2023.1332049, doi:10.3389/fcell.2023.1332049. This article has 33 citations and is from a poor quality or predatory journal.
(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.
(song2024posttranslationalmodificationsof pages 1-2): Yunjia Song, Ying Qu, Caiyun Mao, Rong Zhang, Deyou Jiang, and Xutao Sun. Post-translational modifications of keap1: the state of the art. Frontiers in Cell and Developmental Biology, Jan 2024. URL: https://doi.org/10.3389/fcell.2023.1332049, doi:10.3389/fcell.2023.1332049. This article has 33 citations and is from a poor quality or predatory journal.
(chen2024keap1nrf2pathwaya pages 2-4): 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.
(verza2025theimpactof pages 4-5): FLáVIA ALVES VERZA, GUILHERME CARVALHO DA SILVA, and FELIPE GARCIA NISHIMURA. The impact of oxidative stress and the nrf2-keap1-are signaling pathway on anticancer drug resistance. Oncology Research, 33:1819-1834, Jul 2025. URL: https://doi.org/10.32604/or.2025.065755, doi:10.32604/or.2025.065755. This article has 6 citations and is from a peer-reviewed journal.
(wang2024aconservednterminal pages 1-2): Weize Wang, Ling Liang, Zonglin Dai, Peng Zuo, Shang Yu, Yishuo Lu, Dian Ding, Hongyi Chen, Hui Shan, Yan Jin, Youdong Mao, and Yuxin Yin. A conserved n-terminal motif of cul3 contributes to assembly and e3 ligase activity of crl3klhl22. Nature Communications, May 2024. URL: https://doi.org/10.1038/s41467-024-48045-2, doi:10.1038/s41467-024-48045-2. This article has 10 citations and is from a highest quality peer-reviewed journal.
(hu2024dynamicmoleculararchitecture pages 1-21): Yuxia Hu, Zhao Zhang, Qiyu Mao, Xiang Zhang, Aihua Hao, Yu Xun, Yeda Wang, Lin Han, Wuqiang Zhan, Qianying Liu, Yue Yin, Chao Peng, Eva Marie Y. Moresco, Zhenguo Chen, Bruce Beutler, and Lei Sun. Dynamic molecular architecture and substrate recruitment of cullin3-ring e3 ligase crl3kbtbd2. Nature structural & molecular biology, 31:336-350, Feb 2024. URL: https://doi.org/10.1038/s41594-023-01182-6, doi:10.1038/s41594-023-01182-6. This article has 17 citations and is from a highest quality peer-reviewed journal.
(bi2024genomewideanalysesreveal pages 1-2): Wenjian Bi, Zhiyu Xu, Feng Liu, Zhi Xie, Hao Liu, Xiaotian Zhu, Wenge Zhong, Peipei Zhang, and Xing Tang. Genome-wide analyses reveal the contribution of somatic variants to the immune landscape of multiple cancer types. PLOS Genetics, 20:e1011134, Jan 2024. URL: https://doi.org/10.1371/journal.pgen.1011134, doi:10.1371/journal.pgen.1011134. This article has 1 citations and is from a domain leading peer-reviewed journal.
(wei2024redoxhighphenotypemediated pages 1-2): Xue-Wu Wei, Chang Lu, Yi-Chen Zhang, Xue Fan, Chong-Rui Xu, Zhi-Hong Chen, Fen Wang, Xiao-Rong Yang, Jia-Yi Deng, Ming-Yi Yang, Qing Gou, Shi-Qi Mei, Wei-Chi Luo, Ri-Wei Zhong, Wen-Zhao Zhong, Jin-Ji Yang, Xu-Chao Zhang, Hai-Yan Tu, Yi-Long Wu, and Qing Zhou. Redoxhigh phenotype mediated by keap1/stk11/smarca4/nrf2 mutations diminishes tissue-resident memory cd8+ t cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma. Oncoimmunology, Apr 2024. URL: https://doi.org/10.1080/2162402x.2024.2340154, doi:10.1080/2162402x.2024.2340154. This article has 20 citations and is from a domain leading peer-reviewed journal.

Citations

verza2025theimpactof pages 4-5
song2024posttranslationalmodificationsof pages 1-2
wang2024aconservednterminal pages 1-2
hu2024dynamicmoleculararchitecture pages 1-21
bi2024genomewideanalysesreveal pages 1-2
wei2024redoxhighphenotypemediated pages 1-2
song2024posttranslationalmodificationsof pages 2-3
https://doi.org/10.1016/j.redox.2023.102726
https://doi.org/10.5937/arhfarm73-43475
https://doi.org/10.1152/physrev.00023.2017
https://doi.org/10.3389/fonc.2024.1381467
https://doi.org/10.3389/fcell.2023.1332049
https://doi.org/10.3390/antiox13040400
https://doi.org/10.3390/ijms25063521
https://doi.org/10.1038/s41467-024-48045-2
https://doi.org/10.1038/s41594-023-01182-6
https://doi.org/10.1111/cas.16355
https://doi.org/10.1371/journal.pgen.1011134
https://doi.org/10.1080/2162402x.2024.2340154
https://doi.org/10.3390/ijms25063510
https://doi.org/10.1016/j.redox.2023.102726,
https://doi.org/10.5937/arhfarm73-43475,
https://doi.org/10.3389/fcell.2023.1332049,
https://doi.org/10.3389/fonc.2024.1381467,
https://doi.org/10.32604/or.2025.065755,
https://doi.org/10.1038/s41467-024-48045-2,
https://doi.org/10.1038/s41594-023-01182-6,
https://doi.org/10.1371/journal.pgen.1011134,
https://doi.org/10.1080/2162402x.2024.2340154,

Bioreason Rl Review

(KEAP1-bioreason-rl-review.md)

BioReason-Pro RL Review: KEAP1 (human)

Source: KEAP1-deep-research-bioreason-rl.md

Correctness: 3/5
Completeness: 2/5

Functional Summary Review

The BioReason functional summary states:

A cytoplasmic BTB-Kelch scaffold that dimerizes through an N-terminal BTB/POZ core and uses an adjacent BACK segment to assemble ubiquitin-ligase modules, while a C-terminal Kelch beta-propeller binds substrates and actin-associated factors. This architecture enables multivalent protein binding that coordinates cytoskeletal remodeling with selective substrate recruitment, supporting dynamic organization of actin structures and tuning of cytoplasmic signaling pathways.

The identification of BTB/POZ, BACK, and Kelch domains is correct, and the inference that this is a CUL3-based E3 ubiquitin ligase adaptor is partially captured. However, BioReason focuses heavily on "cytoskeletal remodeling" and "actin structures," which is a significant mischaracterization of KEAP1's primary function.

The curated review describes KEAP1 as "a cysteine-rich substrate adaptor for a CUL3-dependent E3 ubiquitin ligase complex" whose primary role is sensing oxidative/electrophilic stress and targeting NRF2 (NFE2L2) for ubiquitin-dependent proteasomal degradation. The Kelch beta-propeller binds the Neh2 domain of NRF2 -- not actin-associated factors. KEAP1's reactive cysteine residues (Cys151, Cys273, Cys288) serve as electrophile sensors that modify KEAP1 conformation, disrupting NRF2 ubiquitination and allowing NRF2 to activate cytoprotective gene expression.

BioReason entirely misses:
1. The KEAP1-NRF2 axis as the central biological function
2. The role as a redox/electrophile sensor
3. The ubiquitin-proteasome pathway (although the thinking trace mentions "ubiquitin-ligase assemblies")
4. Regulation of the antioxidant response

The curated review lists transcription factor binding (GO:0008134) as a molecular function and ubiquitin-dependent protein catabolic process and regulation of transcription as key processes -- none of which appear in BioReason's functional summary.

Comparison with interpro2go:

The curated review references GO_REF:0000033 and GO_REF:0000044 but not GO_REF:0000002 specifically. The BTB-Kelch domain architecture would map via interpro2go to generic protein binding terms. BioReason essentially recapitulates this generic interpro2go-level inference without adding the critical biological context about NRF2 regulation. The "actin cytoskeleton organization" process assignment appears to be an error -- likely caused by the general association of Kelch domains with cytoskeletal proteins in some family members, which does not apply to KEAP1.

Notes on thinking trace

The trace correctly dissects the BTB-BACK-Kelch architecture and mentions cullin-based ubiquitin ligase assembly. However, the pivot to "actin cytoskeleton organization" as the biological process is a significant misinterpretation. The trace seems to generalize from the Kelch superfamily's association with actin in some members (e.g., Kelch protein in Drosophila) rather than deriving the specific NRF2-regulatory function of KEAP1.

📄 View Raw YAML

id: Q14145
gene_symbol: KEAP1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: KEAP1 (Kelch-like ECH-associated protein 1) is a cysteine-rich 
  BTB-BACK-Kelch protein that functions as the principal substrate adaptor of 
  the BCR(KEAP1) E3 ubiquitin ligase complex (CUL3-RBX1-KEAP1). In its 
  homodimeric form, KEAP1 binds the Neh2 domain of NRF2 (NFE2L2) via two degron 
  motifs (ETGE and DLG) and targets NRF2 for polyubiquitination and proteasomal 
  degradation under basal conditions. KEAP1 contains reactive cysteine residues 
  (especially Cys151, Cys273, Cys288) that act as sensors for electrophiles and 
  oxidative stress. Upon covalent modification of these cysteines by 
  electrophilic compounds (sulforaphane, itaconate, etc.) or reactive oxygen 
  species, the E3 ligase activity is inhibited, allowing NRF2 to accumulate and 
  translocate to the nucleus to activate cytoprotective genes via antioxidant 
  response elements (AREs). KEAP1 is primarily cytoplasmic and is also regulated
  by autophagy through interaction with SQSTM1/p62, which sequesters KEAP1 in 
  inclusion bodies. Loss-of-function mutations in KEAP1 are frequent in lung 
  cancer and lead to constitutive NRF2 activation, promoting tumor growth and 
  chemoresistance.
existing_annotations:
  - term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: KEAP1 functions as a substrate adaptor for the CUL3-RBX1 E3 
        ubiquitin ligase complex that targets NRF2 for polyubiquitination and 
        subsequent proteasomal degradation (PMID:15572695, PMID:15601839). This 
        is a well-established core function of KEAP1.
      action: ACCEPT
      reason: This annotation accurately captures KEAP1's role in targeting NRF2
        for ubiquitin-dependent proteasomal degradation. Multiple studies 
        demonstrate that KEAP1 assembles with CUL3 and RBX1 to mediate NRF2 
        ubiquitination (PMID:15572695, PMID:15601839, PMID:15983046).
      supported_by:
        - reference_id: PMID:15572695
          supporting_text: Keap1 is a redox-regulated substrate adaptor protein 
            for a Cul3-dependent ubiquitin ligase complex.
        - reference_id: PMID:15601839
          supporting_text: BTB protein Keap1 targets antioxidant transcription 
            factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase.
        - reference_id: file:human/KEAP1/KEAP1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: KEAP1 is predominantly localized in the cytoplasm where it 
        sequesters NRF2 and targets it for degradation (PMID:15601839, UniProt 
        Q14145).
      action: ACCEPT
      reason: 'Cytoplasmic localization is well established for KEAP1. UniProt states:
        "Mainly cytoplasmic" and this has been confirmed in multiple experimental
        studies (PMID:15601839, PMID:19424503).'
      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:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: KEAP1 functions as a substrate adaptor protein for the 
        CUL3-dependent E3 ubiquitin ligase complex, recruiting NRF2 for 
        ubiquitination (PMID:15572695, PMID:15601839).
      action: ACCEPT
      reason: This is the core molecular function of KEAP1. KEAP1 binds CUL3 via
        its BTB domain and recruits substrates (primarily NRF2) via its Kelch 
        domain (PMID:15572695, PMID:15601839).
      supported_by:
        - reference_id: PMID:15572695
          supporting_text: Keap1 is a redox-regulated substrate adaptor protein 
            for a Cul3-dependent ubiquitin ligase complex.
        - 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:0031463
      label: Cul3-RING ubiquitin ligase complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: KEAP1 is a component of the CUL3-RING ubiquitin ligase complex 
        (CRL3), where it serves as the substrate adaptor recruiting NRF2 
        (PMID:15572695, PMID:15601839, PMID:15983046).
      action: ACCEPT
      reason: 'Well-established that KEAP1 is part of the CRL3 complex. UniProt states:
        "Component of the BCR(KEAP1) E3 ubiquitin ligase complex, at least composed
        of 2 molecules of CUL3, 2 molecules of KEAP1, and RBX1."'
      supported_by:
        - reference_id: PMID:15572695
          supporting_text: Keap1 is a redox-regulated substrate adaptor protein 
            for a Cul3-dependent ubiquitin ligase complex.
        - 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: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: KEAP1 has been detected in the nucleus in some studies, though it
        is predominantly cytoplasmic. UniProt reports nuclear localization based
        on PMID:15657435.
      action: KEEP_AS_NON_CORE
      reason: While KEAP1 is predominantly cytoplasmic, some studies have 
        detected it in the nucleus. This is not the primary site of function but
        represents a secondary localization.
      supported_by:
        - reference_id: UniProt:Q14145
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: KEAP1 is primarily cytoplasmic, where it functions to sequester 
        and target NRF2 for degradation.
      action: ACCEPT
      reason: Cytoplasmic localization is the established primary location for 
        KEAP1 function. This is consistent with the IBA annotation and 
        experimental evidence.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16189514
    review:
      summary: High-throughput protein-protein interaction study. The specific 
        interactor is ETF1 (eukaryotic translation termination factor 1).
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding annotation from high-throughput study. The
        meaningful biological significance of KEAP1-ETF1 interaction is unclear 
        and not related to KEAP1's core function in NRF2 regulation.
      supported_by:
        - reference_id: PMID:16189514
          supporting_text: Towards a proteome-scale map of the human 
            protein-protein interaction network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16888629
    review:
      summary: Structural study demonstrating the KEAP1-NRF2 interaction 
        interface. The interactor is NRF2 (NFE2L2, Q16236).
      action: MODIFY
      reason: While this demonstrates a real and important interaction with 
        NRF2, "protein binding" is uninformative. A more specific term should be
        used.
      proposed_replacement_terms:
        - id: GO:0061629
          label: RNA polymerase II-specific DNA-binding transcription factor 
            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: Study demonstrating KEAP1 interaction with NRF2 and the role of 
        DJ-1 in this interaction. The interactor is NRF2 (Q16236).
      action: MODIFY
      reason: This represents the functionally important KEAP1-NRF2 interaction.
        Should be annotated with a more specific term reflecting the regulatory 
        relationship.
      proposed_replacement_terms:
        - id: GO:0061629
          label: RNA polymerase II-specific DNA-binding transcription factor 
            binding
      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:17510365
    review:
      summary: Study on WTX (AMER1) interaction. WTX interacts with multiple 
        proteins including KEAP1.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding annotation. The functional significance of
        KEAP1-AMER1/WTX interaction is not related to KEAP1's core function.
      supported_by:
        - reference_id: PMID:17510365
          supporting_text: Wilms tumor suppressor WTX negatively regulates 
            WNT/beta-catenin signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18757741
    review:
      summary: Study on cancer-related NRF2 mutations that impair KEAP1 
        recognition. Interactor is NRF2 (Q16236).
      action: MODIFY
      reason: Demonstrates the critical KEAP1-NRF2 interaction and how cancer 
        mutations disrupt it. Should use more specific term.
      proposed_replacement_terms:
        - id: GO:0061629
          label: RNA polymerase II-specific DNA-binding transcription factor 
            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:19615732
    review:
      summary: Deubiquitinating enzyme interaction landscape study. Multiple 
        interactors identified including ETF1, MAD2L1, SQSTM1, DPP3, and others.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput interaction study. Generic protein binding is 
        uninformative for these various interactors.
      supported_by:
        - reference_id: PMID:19615732
          supporting_text: Jul 16. Defining the human deubiquitinating enzyme 
            interaction landscape.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19706542
    review:
      summary: Study on nitric oxide activation of KEAP1/NRF2 signaling. 
        Interactor is NRF2.
      action: MODIFY
      reason: Represents KEAP1-NRF2 core regulatory interaction. Should use more
        specific term.
      proposed_replacement_terms:
        - id: GO:0061629
          label: RNA polymerase II-specific DNA-binding transcription factor 
            binding
      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:20173742
    review:
      summary: Study on p62/SQSTM1 activation of NRF2 through KEAP1 
        inactivation. Interactors include SQSTM1.
      action: ACCEPT
      reason: SQSTM1/p62 interaction with KEAP1 is functionally important for 
        autophagy- mediated regulation of the KEAP1-NRF2 pathway. This is 
        well-established.
      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: PMID:20173742
          supporting_text: The selective autophagy substrate p62 activates the 
            stress responsive transcription factor Nrf2 through inactivation of 
            Keap1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20452972
    review:
      summary: Detailed study on p62/SQSTM1-KEAP1 interaction and its role in 
        autophagy- mediated NRF2 activation. Interactor is SQSTM1 (Q13501).
      action: ACCEPT
      reason: The SQSTM1-KEAP1 interaction is functionally important and 
        represents a key regulatory mechanism linking autophagy to oxidative 
        stress response. Well characterized interaction.
      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:20562859
    review:
      summary: Network organization of autophagy system study. Interactor is 
        SQSTM1.
      action: ACCEPT
      reason: SQSTM1/p62-KEAP1 interaction is a genuine and functionally 
        relevant interaction for autophagy regulation.
      supported_by:
        - reference_id: PMID:20562859
          supporting_text: Network organization of the human autophagy system.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20600852
    review:
      summary: Study on KEAP1 suppression of NF-kappaB signaling via IKKbeta 
        regulation. Interactors include IKBKB.
      action: KEEP_AS_NON_CORE
      reason: KEAP1-IKKbeta interaction may represent a secondary function 
        related to NF-kappaB regulation, but this is not the primary function of
        KEAP1.
      supported_by:
        - reference_id: PMID:20600852
          supporting_text: 2010 Jun 20. Suppression of NF-kappaB signaling by 
            KEAP1 regulation of IKKbeta activity through autophagic degradation 
            and inhibition of phosphorylation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21044950
    review:
      summary: Telomere signaling study. Interactor is TERF1.
      action: MARK_AS_OVER_ANNOTATED
      reason: The functional significance of KEAP1-TERF1 interaction is unclear 
        and not related to KEAP1's established functions.
      supported_by:
        - reference_id: PMID:21044950
          supporting_text: Epub 2010 Nov 2. Genome-wide YFP fluorescence 
            complementation screen identifies new regulators for telomere 
            signaling in human cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21145461
    review:
      summary: Cullin-RING ubiquitin ligase network study. Interactor is CUL3 
        (Q13618).
      action: ACCEPT
      reason: CUL3 is the scaffold protein that KEAP1 binds to form the 
        BCR(KEAP1) E3 ligase complex. This is a core functional interaction.
      supported_by:
        - reference_id: PMID:15572695
          supporting_text: Keap1 is a redox-regulated substrate adaptor protein 
            for a Cul3-dependent ubiquitin ligase complex.
        - reference_id: PMID:21145461
          supporting_text: Dynamics of cullin-RING ubiquitin ligase network 
            revealed by systematic quantitative proteomics.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21516116
    review:
      summary: Next-generation sequencing interactome study. Interactor is DPP3.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput study. The DPP3-KEAP1 interaction significance is 
        unclear.
      supported_by:
        - reference_id: PMID:21516116
          supporting_text: Next-generation sequencing to generate interactome 
            datasets.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21903422
    review:
      summary: Innate immunity interaction network study. Interactor is IRF1.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput study; functional significance unclear for KEAP1 
        core function.
      supported_by:
        - reference_id: PMID:21903422
          supporting_text: 2011 Sep 8. Mapping a dynamic innate immunity protein
            interaction network regulating type I interferon production.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21988832
    review:
      summary: Human liver protein interaction network study. Multiple 
        interactors including NRF2, NFE2L1, and others.
      action: ACCEPT
      reason: Includes the important NRF2 interaction which is core to KEAP1 
        function.
      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:23274085
    review:
      summary: Study on Sestrins activating NRF2 by promoting p62-dependent 
        autophagic degradation of KEAP1. Interactor is SESN2 (P58004).
      action: ACCEPT
      reason: SESN2-KEAP1 interaction is functionally relevant for 
        autophagy-mediated regulation of KEAP1-NRF2 signaling.
      supported_by:
        - reference_id: PMID:23274085
          supporting_text: Dec 27. Sestrins activate Nrf2 by promoting 
            p62-dependent autophagic degradation of Keap1 and prevent oxidative 
            liver damage.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: Large-scale human interactome mapping. Multiple interactors 
        identified.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput study with many interactors; generic protein 
        binding is uninformative.
      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: Study on CUL3-KBTBD6/7 ubiquitin ligase. Interactor is NRF2.
      action: MODIFY
      reason: NRF2 interaction should use more specific term.
      proposed_replacement_terms:
        - id: GO:0061629
          label: RNA polymerase II-specific DNA-binding transcription factor 
            binding
      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:25910212
    review:
      summary: Study on genetic disorder-associated interaction perturbations. 
        Multiple interactors including SQSTM1.
      action: ACCEPT
      reason: Includes SQSTM1 interaction which is functionally important.
      supported_by:
        - reference_id: PMID:25910212
          supporting_text: Widespread macromolecular interaction perturbations 
            in human genetic disorders.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27107014
    review:
      summary: Inter-species protein interaction network study.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput cross-species study; generic annotation.
      supported_by:
        - reference_id: PMID:27107014
          supporting_text: An inter-species protein-protein interaction network 
            across vast evolutionary distance.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29792731
    review:
      summary: APR3 modulation of oxidative stress. Interactor is NRF2.
      action: MODIFY
      reason: NRF2 interaction should use more specific term.
      proposed_replacement_terms:
        - id: GO:0061629
          label: RNA polymerase II-specific DNA-binding transcription factor 
            binding
      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:30190310
    review:
      summary: Dimerization quality control study. Interactor is KLHL2 (O95198).
      action: ACCEPT
      reason: KLHL2 is a related BTB-Kelch family member; interaction may 
        reflect heterodimerization potential.
      supported_by:
        - reference_id: PMID:30190310
          supporting_text: 2018 Sep 6. Dimerization quality control ensures 
            neuronal development and survival.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31169361
    review:
      summary: Peptidomic study on KEAP1 peptide epitope interactions. Multiple 
        interactors.
      action: MARK_AS_OVER_ANNOTATED
      reason: Methodological study on peptide binding; generic annotation.
      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: Study on FAM129B/NIBAN2 competing with NRF2 for KEAP1 binding. 
        Interactors include NRF2 and NIBAN2.
      action: ACCEPT
      reason: NIBAN2 competition for KEAP1 binding represents a regulatory 
        mechanism for NRF2 activation.
      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: Study on genetic variant effects on protein interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput variant study; generic annotation.
      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 human binary protein interactome map. Many interactors 
        identified.
      action: MARK_AS_OVER_ANNOTATED
      reason: Large-scale interactome study; generic protein binding is 
        uninformative.
      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:32814053
    review:
      summary: Neurodegenerative disease protein interactome study.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput study; generic annotation.
      supported_by:
        - reference_id: PMID:32814053
          supporting_text: Interactome Mapping Provides a Network of 
            Neurodegenerative Disease Proteins and Uncovers Widespread Protein 
            Aggregation in Affected Brains.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32911434
    review:
      summary: High-density NRF2 interactome study. Interactor is NRF2 (Q16236).
      action: MODIFY
      reason: NRF2 interaction should use more specific term.
      proposed_replacement_terms:
        - id: GO:0061629
          label: RNA polymerase II-specific DNA-binding transcription factor 
            binding
      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 interactome network study.
      action: MARK_AS_OVER_ANNOTATED
      reason: Large-scale interactome study; generic annotation.
      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:34591612
    review:
      summary: Breast cancer protein interaction landscape study.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput cancer interactome study; generic annotation.
      supported_by:
        - reference_id: PMID:34591612
          supporting_text: Oct 1. A protein interaction landscape of breast 
            cancer.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:34591642
    review:
      summary: Head and neck cancer protein network study.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput cancer interactome study; generic annotation.
      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:35044719
    review:
      summary: Proteome-scale binding site mapping in unstructured regions.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput binding study; generic annotation.
      supported_by:
        - reference_id: PMID:35044719
          supporting_text: Proteome-scale mapping of binding sites in the 
            unstructured regions of the human proteome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35512704
    review:
      summary: Cancer mutation-directed neo-interaction discovery. Interactors 
        include BRAF and NRF2.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput study; generic annotation.
      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:37187359
    review:
      summary: Geniposide effects on KEAP1-NRF2 signaling in colitis. Interactor
        is NRF2.
      action: MODIFY
      reason: NRF2 interaction should use more specific term.
      proposed_replacement_terms:
        - id: GO:0061629
          label: RNA polymerase II-specific DNA-binding transcription factor 
            binding
      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:39009827
    review:
      summary: Proteome-scale motif-based interaction rewiring by disease 
        mutations.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput study; generic annotation.
      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:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: Multimodal cell maps study.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput structural/functional genomics study; generic 
        annotation.
      supported_by:
        - reference_id: PMID:40205054
          supporting_text: Apr 9. Multimodal cell maps as a foundation for 
            structural and functional genomics.
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Transferred from mouse ortholog. Some KEAP1 may localize to ER, 
        possibly related to interaction with NFE2L1 which has ER localization.
      action: KEEP_AS_NON_CORE
      reason: KEAP1 is primarily cytoplasmic but may have minor ER localization 
        related to NFE2L1 regulation. Not a primary localization.
  - term:
      id: GO:0005884
      label: actin filament
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Transferred from mouse ortholog. KEAP1 may associate with actin 
        cytoskeleton.
      action: KEEP_AS_NON_CORE
      reason: KEAP1 has been reported to associate with the actin cytoskeleton, 
        but this is not its primary localization.
  - term:
      id: GO:0006511
      label: ubiquitin-dependent protein catabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: KEAP1 participates in ubiquitin-dependent protein catabolism by 
        targeting NRF2 for ubiquitination.
      action: ACCEPT
      reason: This is a core function of KEAP1. The more specific term 
        GO:0043161 (proteasome-mediated) is also annotated.
  - term:
      id: GO:0010506
      label: regulation of autophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: KEAP1 is involved in autophagy regulation through its interaction
        with SQSTM1/p62 (PMID:20452972).
      action: ACCEPT
      reason: KEAP1 is regulated by and participates in autophagy through 
        SQSTM1/p62 interaction, which sequesters KEAP1 in inclusion bodies.
      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:0016234
      label: inclusion body
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: KEAP1 localizes to inclusion bodies through interaction with 
        SQSTM1/p62 during selective autophagy.
      action: ACCEPT
      reason: KEAP1 relocalizes to p62/SQSTM1-positive inclusion bodies during 
        autophagy activation (PMID:20452972).
      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:0016567
      label: protein ubiquitination
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: KEAP1 is involved in protein ubiquitination as the substrate 
        adaptor for the CRL3 complex.
      action: ACCEPT
      reason: This is a core function of KEAP1, which targets NRF2 (and other 
        substrates) for ubiquitination.
  - term:
      id: GO:0031463
      label: Cul3-RING ubiquitin ligase complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: KEAP1 is a component of the CUL3-RING ubiquitin ligase complex.
      action: ACCEPT
      reason: Duplicate of IBA annotation. KEAP1 is established as part of the 
        CRL3 complex.
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: KEAP1 is part of protein complexes including the BCR(KEAP1) E3 
        ligase complex.
      action: MARK_AS_OVER_ANNOTATED
      reason: This is an overly generic term. More specific terms like 
        GO:0031463 (Cul3-RING ubiquitin ligase complex) are already annotated.
  - term:
      id: GO:0034599
      label: cellular response to oxidative stress
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: KEAP1 is the key sensor and regulator of cellular response to 
        oxidative stress through NRF2 regulation.
      action: ACCEPT
      reason: This is a core function of KEAP1. KEAP1's cysteine sensors detect 
        oxidative stress and electrophiles, leading to NRF2 stabilization and 
        cytoprotective gene expression.
      supported_by:
        - reference_id: PMID:15572695
          supporting_text: Keap1 is a redox-regulated substrate adaptor protein 
            for a Cul3-dependent ubiquitin ligase complex.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: KEAP1 homodimerizes via its BTB domain to form the functional 
        substrate adaptor for the CRL3 complex.
      action: ACCEPT
      reason: KEAP1 homodimerization is essential for its function. The 
        BCR(KEAP1) complex contains 2 molecules of KEAP1 (UniProt).
      supported_by:
        - reference_id: UniProt:Q14145
  - term:
      id: GO:0097718
      label: disordered domain specific binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: KEAP1's Kelch domain binds the intrinsically disordered Neh2 
        domain of NRF2 via ETGE and DLG motifs.
      action: ACCEPT
      reason: KEAP1 binds the disordered Neh2 domain of NRF2, which contains the
        ETGE and DLG degron motifs.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: Human Protein Atlas immunofluorescence data indicates some KEAP1 
        in nucleoplasm.
      action: KEEP_AS_NON_CORE
      reason: KEAP1 is primarily cytoplasmic but may have minor nuclear 
        localization. This is not the primary site of function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: Human Protein Atlas immunofluorescence confirms cytosolic 
        localization of KEAP1.
      action: ACCEPT
      reason: Cytosolic localization is well established for KEAP1.
  - term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    evidence_type: IDA
    original_reference_id: PMID:29249570
    review:
      summary: Review on CUL3-based ubiquitin ligases confirms KEAP1's role in 
        proteasomal degradation of substrates.
      action: ACCEPT
      reason: This is a core function of KEAP1. Well-established that KEAP1 
        targets NRF2 for proteasomal degradation.
      supported_by:
        - reference_id: PMID:29249570
          supporting_text: Epub 2017 Dec 14. Cullin 3-Based Ubiquitin Ligases as
            Master Regulators of Mammalian Cell Differentiation.
  - term:
      id: GO:0006511
      label: ubiquitin-dependent protein catabolic process
    evidence_type: IDA
    original_reference_id: PMID:15572695
    review:
      summary: Study demonstrating KEAP1 functions as substrate adaptor for 
        CUL3-dependent ubiquitin ligase targeting NRF2 for degradation 
        (PMID:15572695).
      action: ACCEPT
      reason: Core function of KEAP1 directly demonstrated.
      supported_by:
        - reference_id: PMID:15572695
          supporting_text: Keap1 is a redox-regulated substrate adaptor protein 
            for a Cul3-dependent ubiquitin ligase complex.
  - term:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:15572695
    review:
      summary: Directly demonstrates KEAP1 as substrate adaptor for CUL3-RBX1 E3
        ligase (PMID:15572695).
      action: ACCEPT
      reason: Core molecular function directly demonstrated.
      supported_by:
        - reference_id: PMID:15572695
          supporting_text: Keap1 is a redox-regulated substrate adaptor protein 
            for a Cul3-dependent ubiquitin ligase complex.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:36882524
    review:
      summary: Study on C4orf19/PGCKA1 competing with TRIM25 for KEAP1 binding. 
        Interactor is PGCKA1 (Q8IY42).
      action: ACCEPT
      reason: PGCKA1 interaction with KEAP1 is functionally relevant for KEAP1 
        stability regulation.
      supported_by:
        - reference_id: PMID:36882524
          supporting_text: 2023 Mar 7. C4orf19 inhibits colorectal cancer cell 
            proliferation by competitively binding to Keap1 with TRIM25 via the 
            USP17/Elk-1/CDK6 axis.
  - term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    evidence_type: IDA
    original_reference_id: PMID:15601839
    review:
      summary: Study demonstrating KEAP1 targets NRF2 for proteasomal 
        degradation via CUL3-ROC1 ligase (PMID:15601839).
      action: ACCEPT
      reason: Core function directly demonstrated.
      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:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:15601839
    review:
      summary: Study demonstrating KEAP1 functions as substrate adaptor 
        (PMID:15601839).
      action: ACCEPT
      reason: Core function directly demonstrated. Duplicate evidence with 
        PMID:15572695.
      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:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:17015834
    review:
      summary: Study showing KEAP1 negatively regulates NRF2 transcriptional 
        activity (PMID:17015834).
      action: ACCEPT
      reason: KEAP1 negatively regulates NRF2, a transcription factor that 
        activates Pol II-dependent genes. This is achieved through degradation 
        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:0140416
      label: transcription regulator inhibitor activity
    evidence_type: IDA
    original_reference_id: PMID:17015834
    review:
      summary: KEAP1 inhibits NRF2 transcription factor activity by promoting 
        its degradation (PMID:17015834).
      action: ACCEPT
      reason: Core function of KEAP1 as an inhibitor of NRF2 transcriptional 
        activity.
      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:1902883
      label: negative regulation of response to oxidative stress
    evidence_type: IDA
    original_reference_id: PMID:15601839
    review:
      summary: KEAP1 negatively regulates oxidative stress response by targeting
        NRF2 for degradation under basal conditions (PMID:15601839).
      action: ACCEPT
      reason: Core function of KEAP1 - it suppresses the cellular antioxidant 
        response by degrading NRF2 under normal conditions.
      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:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9766645
    review:
      summary: Reactome pathway annotation for KEAP1 cytosolic localization.
      action: ACCEPT
      reason: Cytosolic localization is well established.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9766656
    review:
      summary: Reactome pathway annotation for KEAP1 cytosolic localization.
      action: ACCEPT
      reason: Duplicate cytosol annotation from Reactome.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9766677
    review:
      summary: Reactome pathway annotation for KEAP1 cytosolic localization.
      action: ACCEPT
      reason: Duplicate cytosol annotation from Reactome.
  - term:
      id: GO:0061629
      label: RNA polymerase II-specific DNA-binding transcription factor binding
    evidence_type: IPI
    original_reference_id: PMID:17015834
    review:
      summary: KEAP1 binds NRF2, an RNA Pol II-specific transcription factor, to
        regulate its stability and activity (PMID:17015834).
      action: ACCEPT
      reason: This appropriately captures KEAP1's interaction with NRF2 (a 
        transcription factor) more specifically than generic protein binding.
      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:15601839
    review:
      summary: Demonstrates KEAP1 interaction with NRF2 (Q16236).
      action: MODIFY
      reason: Should use more specific term for NRF2 interaction.
      proposed_replacement_terms:
        - id: GO:0061629
          label: RNA polymerase II-specific DNA-binding transcription factor 
            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:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:15601839
    review:
      summary: Study demonstrates cytoplasmic localization of KEAP1 
        (PMID:15601839).
      action: ACCEPT
      reason: Core localization directly demonstrated.
      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:0006511
      label: ubiquitin-dependent protein catabolic process
    evidence_type: IDA
    original_reference_id: PMID:15601839
    review:
      summary: Study demonstrates KEAP1 role in ubiquitin-dependent degradation 
        (PMID:15601839).
      action: ACCEPT
      reason: Duplicate of earlier annotation; core 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:0010506
      label: regulation of autophagy
    evidence_type: IDA
    original_reference_id: PMID:20452972
    review:
      summary: Study demonstrates KEAP1 involvement in autophagy regulation 
        through SQSTM1/p62 interaction (PMID:20452972).
      action: ACCEPT
      reason: Well-characterized function of KEAP1 in autophagy regulation.
      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:0016234
      label: inclusion body
    evidence_type: IDA
    original_reference_id: PMID:20452972
    review:
      summary: KEAP1 accumulates in p62-positive inclusion bodies during 
        autophagy (PMID:20452972).
      action: ACCEPT
      reason: Directly demonstrated localization during autophagy activation.
      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:0016567
      label: protein ubiquitination
    evidence_type: IDA
    original_reference_id: PMID:15601839
    review:
      summary: KEAP1 promotes NRF2 ubiquitination (PMID:15601839).
      action: ACCEPT
      reason: Core function directly demonstrated.
      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:0031463
      label: Cul3-RING ubiquitin ligase complex
    evidence_type: IDA
    original_reference_id: PMID:15601839
    review:
      summary: Study identifies KEAP1 as component of CUL3-ROC1 complex 
        (PMID:15601839).
      action: ACCEPT
      reason: Core complex membership directly demonstrated.
      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: IDA
    original_reference_id: PMID:15601839
    review:
      summary: KEAP1 regulates cellular response to oxidative stress by 
        controlling NRF2 levels (PMID:15601839).
      action: ACCEPT
      reason: Core function directly demonstrated.
      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:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26517842
    review:
      summary: Study on HSP90 isoform binding preferences. Interactors include 
        HSP90AA1 (P07900) and HSP90AB1 (P08238).
      action: KEEP_AS_NON_CORE
      reason: HSP90 interaction may represent chaperone-related regulation but 
        is not core to KEAP1 function.
      supported_by:
        - reference_id: PMID:26517842
          supporting_text: eCollection 2015. Client Proteins and Small Molecule 
            Inhibitors Display Distinct Binding Preferences for Constitutive and
            Stress-Induced HSP90 Isoforms and Their Conformationally Restricted 
            Mutants.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6781764
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Cytosol localization is established.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: PMID:17015834
    review:
      summary: Study supports cytosolic localization of KEAP1.
      action: ACCEPT
      reason: Consistent with other evidence.
      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:0032436
      label: positive regulation of proteasomal ubiquitin-dependent protein 
        catabolic process
    evidence_type: TAS
    original_reference_id: PMID:17015834
    review:
      summary: KEAP1 promotes proteasomal degradation of NRF2 (PMID:17015834).
      action: ACCEPT
      reason: Core function of KEAP1 as a positive regulator of NRF2 proteasomal
        degradation.
      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:24089205
    review:
      summary: Study on autophagy and primary ciliogenesis. Interactor is OFD1 
        (Q9GZQ8) indirectly via MAP1LC3B.
      action: KEEP_AS_NON_CORE
      reason: MAP1LC3B/LC3 interaction is relevant to autophagy regulation but 
        not core to KEAP1's primary NRF2-regulatory function.
      supported_by:
        - reference_id: PMID:24089205
          supporting_text: Autophagy promotes primary ciliogenesis by removing 
            OFD1 from centriolar satellites.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19424503
    review:
      summary: Study on ENC1/Ectodermal-neural cortex 1 regulation of NRF2. 
        Interactor is ENC1 (O14682).
      action: KEEP_AS_NON_CORE
      reason: ENC1 interaction with KEAP1 may modulate NRF2 regulation but is 
        not the core interaction.
      supported_by:
        - reference_id: PMID:19424503
          supporting_text: Ectodermal-neural cortex 1 down-regulates Nrf2 at the
            translational level.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:19424503
    review:
      summary: Study confirms cytoplasmic localization.
      action: ACCEPT
      reason: Additional evidence for cytoplasmic localization.
      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: Study on KEAP1 ubiquitination and its role in the ubiquitin 
        ligase complex (PMID:15983046).
      action: ACCEPT
      reason: Core function directly demonstrated.
      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:0031463
      label: Cul3-RING ubiquitin ligase complex
    evidence_type: IDA
    original_reference_id: PMID:15983046
    review:
      summary: Study confirms KEAP1 as component of CUL3-dependent complex 
        (PMID:15983046).
      action: ACCEPT
      reason: Core complex membership confirmed.
      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:0030496
      label: midbody
    evidence_type: IDA
    original_reference_id: PMID:15166316
    review:
      summary: Midbody proteome study identified KEAP1 among midbody proteins 
        (PMID:15166316).
      action: KEEP_AS_NON_CORE
      reason: KEAP1 was identified in a midbody proteome study, but this is a 
        high-throughput proteomic identification and midbody localization is not
        a core aspect of KEAP1 function. KEAP1's primary function is in the 
        cytoplasm regulating NRF2.
      supported_by:
        - reference_id: PMID:15166316
          supporting_text: May 27. Dissection of the mammalian midbody proteome 
            reveals conserved cytokinesis mechanisms.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8932327
    review:
      summary: Reactome pathway annotation for cytosol localization.
      action: ACCEPT
      reason: Consistent with established cytosolic localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8952630
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8952631
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8955241
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8955289
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8956040
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9712274
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9755505
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9755507
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9758090
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9759169
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9759172
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9766687
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9796040
    review:
      summary: Reactome pathway annotation.
      action: ACCEPT
      reason: Consistent with established localization.
core_functions:
  - molecular_function:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    description: KEAP1 functions as the substrate-recognition component 
      (substrate adaptor) of the CUL3-RBX1 E3 ubiquitin ligase complex. It binds
      CUL3 via its BTB domain and recruits substrates (primarily NRF2) via its 
      Kelch domain.
    supported_by:
      - reference_id: PMID:15572695
        supporting_text: Keap1 functions as a substrate adaptor protein for a 
          Cul3-dependent E3 ubiquitin ligase complex
      - reference_id: PMID:15601839
        supporting_text: Here we report that the human BTB-Kelch protein Keap1, 
          a negative regulator of the antioxidative transcription factor Nrf2, 
          binds to CUL3 and Nrf2 via its BTB and Kelch domains, respectively
  - molecular_function:
      id: GO:0140416
      label: transcription regulator inhibitor activity
    description: KEAP1 inhibits NRF2 (NFE2L2), a master transcription factor 
      regulating antioxidant and cytoprotective gene expression. Under basal 
      conditions, KEAP1 targets NRF2 for ubiquitination and proteasomal 
      degradation, thereby inhibiting NRF2-mediated transcription.
    supported_by:
      - reference_id: PMID:17015834
        supporting_text: DJ-1 stabilizes Nrf2 by preventing association with its
          inhibitor protein, Keap1
      - reference_id: PMID:15601839
        supporting_text: We suggest that Keap1 negatively regulates Nrf2 
          function in part by targeting Nrf2 for ubiquitination
references:
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary 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:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:15166316
    title: Dissection of the mammalian midbody proteome reveals conserved 
      cytokinesis mechanisms.
    findings:
      - statement: KEAP1 identified in midbody proteome by mass spectrometry
        supporting_text: Midbodies were isolated from mammalian cells, proteins 
          were identified by multidimensional protein identification technology 
          (MudPIT)
  - id: PMID:15572695
    title: Keap1 is a redox-regulated substrate adaptor protein for a 
      Cul3-dependent ubiquitin ligase complex.
    findings:
      - statement: KEAP1 functions as substrate adaptor for CUL3-dependent E3 
          ubiquitin ligase
        supporting_text: Keap1 functions as a substrate adaptor protein for a 
          Cul3-dependent E3 ubiquitin ligase complex
      - statement: KEAP1 assembles with CUL3 and RBX1 to target NRF2 for 
          ubiquitination
        supporting_text: Keap1 assembles into a functional E3 ubiquitin ligase 
          complex with Cul3 and Rbx1 that targets multiple lysine residues 
          located in the N-terminal Neh2 domain of Nrf2 for ubiquitin 
          conjugation
      - statement: Cys151 is critical for KEAP1 function
        supporting_text: A mutant Keap1 protein containing a single 
          cysteine-to-serine substitution at residue 151 within the BTB domain 
          of Keap1 is markedly resistant to inhibition
  - 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
        supporting_text: Here we report that the human BTB-Kelch protein Keap1, 
          a negative regulator of the antioxidative transcription factor Nrf2, 
          binds to CUL3 and Nrf2 via its BTB and Kelch domains, respectively
      - statement: KEAP1-CUL3-ROC1 complex promotes NRF2 ubiquitination
        supporting_text: The KEAP1-CUL3-ROC1 complex promoted NRF2 
          ubiquitination in vitro
      - statement: Knocking down KEAP1 or CUL3 results in NRF2 accumulation
        supporting_text: Blocking NRF2 degradation in cells expressing both 
          KEAP1 and NRF2 by either inhibiting the proteasome activity or 
          knocking down Cul3, resulted in NRF2 accumulation in the cytoplasm
  - 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:
      - statement: KEAP1 is ubiquitinated by a CUL3-dependent complex
        supporting_text: Keap1 is a BTB-Kelch protein that functions as a 
          substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase 
          complex
      - statement: Oxidative stress increases KEAP1 ubiquitination
        supporting_text: Ubiquitination of Keap1 is markedly increased in cells 
          exposed to quinone-induced oxidative stress
      - statement: KEAP1 degradation is proteasome-independent
        supporting_text: Degradation of Keap1 is independent of the 26 S 
          proteasome, because inhibitors of the 26 S proteasome do not prevent 
          loss of Keap1 following exposure of cells to quinone-induced oxidative
          stress
  - id: PMID:17015834
    title: DJ-1, a cancer- and Parkinson's disease-associated protein, 
      stabilizes the antioxidant transcriptional master regulator Nrf2.
    findings:
      - statement: DJ-1 stabilizes NRF2 by preventing KEAP1 association
        supporting_text: DJ-1 stabilizes Nrf2 by preventing association with its
          inhibitor protein, Keap1
      - statement: KEAP1 promotes NRF2 ubiquitination
        supporting_text: DJ-1 stabilizes Nrf2 by preventing association with its
          inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination
  - 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: p62/SQSTM1 docks onto KEAP1 Kelch domain via KIR motif
        supporting_text: p62 docks directly onto the Kelch-repeat domain of 
          Kelch-like ECH-associated protein 1 (KEAP1), via a motif designated 
          the KEAP1 interacting region (KIR)
      - statement: KEAP1-p62 interaction leads to KEAP1 accumulation in p62 
          bodies
        supporting_text: because p62 is polymeric the interaction between KEAP1 
          and p62 leads to accumulation of KEAP1 in p62 bodies
      - statement: KEAP1 undergoes autophagic degradation via p62 interaction
        supporting_text: the interaction between KEAP1 and p62 leads to 
          accumulation of KEAP1 in p62 bodies, which is followed by autophagic 
          degradation of KEAP1
  - id: PMID:29249570
    title: Cullin 3-Based Ubiquitin Ligases as Master Regulators of Mammalian 
      Cell Differentiation.
    findings:
      - statement: Review on CRL3 complexes including KEAP1-containing complexes
        supporting_text: Based on studies about differentiation programs of 
          mesenchymal stem cells (MSCs), including myogenesis, neurogenesis, 
          chondrogenesis, osteogenesis and adipogenesis, we propose here that 
          CRL3 complexes evolved to fulfill a pivotal role in mammalian cell 
          differentiation
  - id: UniProt:Q14145
    title: UniProt entry for KEAP1
    findings:
      - statement: Comprehensive functional annotation of KEAP1
        supporting_text: Component of the BCR(KEAP1) E3 ubiquitin ligase 
          complex, at least composed of 2 molecules of CUL3, 2 molecules of 
          KEAP1, and RBX1
  - id: PMID:16189514
    title: Towards a proteome-scale map of the human protein-protein interaction
      network.
    findings: []
  - id: PMID:16888629
    title: Structure of the Keap1:Nrf2 interface provides mechanistic insight 
      into Nrf2 signaling.
    findings: []
  - id: PMID:17510365
    title: Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin 
      signaling.
    findings: []
  - id: PMID:18757741
    title: Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3
      E3 ligase and promote malignancy.
    findings: []
  - id: PMID:19424503
    title: Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational 
      level.
    findings: []
  - id: PMID:19615732
    title: Defining the human deubiquitinating enzyme interaction landscape.
    findings: []
  - id: PMID:19706542
    title: Nitric oxide activation of Keap1/Nrf2 signaling in human colon 
      carcinoma cells.
    findings: []
  - id: PMID:20173742
    title: The selective autophagy substrate p62 activates the stress responsive
      transcription factor Nrf2 through inactivation of Keap1.
    findings: []
  - id: PMID:20562859
    title: Network organization of the human autophagy system.
    findings: []
  - id: PMID:20600852
    title: Suppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta 
      activity through autophagic degradation and inhibition of phosphorylation.
    findings: []
  - id: PMID:21044950
    title: Genome-wide YFP fluorescence complementation screen identifies new 
      regulators for telomere signaling in human cells.
    findings: []
  - id: PMID:21145461
    title: Dynamics of cullin-RING ubiquitin ligase network revealed by 
      systematic quantitative proteomics.
    findings: []
  - id: PMID:21516116
    title: Next-generation sequencing to generate interactome datasets.
    findings: []
  - id: PMID:21903422
    title: Mapping a dynamic innate immunity protein interaction network 
      regulating type I interferon production.
    findings: []
  - id: PMID:21988832
    title: Toward an understanding of the protein interaction network of the 
      human liver.
    findings: []
  - id: PMID:23274085
    title: Sestrins activate Nrf2 by promoting p62-dependent autophagic 
      degradation of Keap1 and prevent oxidative liver damage.
    findings: []
  - id: PMID:24089205
    title: Autophagy promotes primary ciliogenesis by removing OFD1 from 
      centriolar satellites.
    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:25910212
    title: Widespread macromolecular interaction perturbations in human genetic 
      disorders.
    findings: []
  - id: PMID:26517842
    title: Client Proteins and Small Molecule Inhibitors Display Distinct 
      Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and
      Their Conformationally Restricted Mutants.
    findings: []
  - id: PMID:27107014
    title: An inter-species protein-protein interaction network across vast 
      evolutionary distance.
    findings: []
  - id: PMID:29792731
    title: APR3 modulates oxidative stress and mitochondrial function in ARPE-19
      cells.
    findings: []
  - id: PMID:30190310
    title: Dimerization quality control ensures neuronal development and 
      survival.
    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:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
      Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
    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:34591612
    title: A protein interaction landscape of breast cancer.
    findings: []
  - id: PMID:34591642
    title: A protein network map of head and neck cancer reveals PIK3CA mutant 
      drug sensitivity.
    findings: []
  - id: PMID:35044719
    title: Proteome-scale mapping of binding sites in the unstructured regions 
      of the human proteome.
    findings: []
  - id: PMID:35512704
    title: Systematic discovery of mutation-directed neo-protein-protein 
      interactions in cancer.
    findings: []
  - id: PMID:36882524
    title: C4orf19 inhibits colorectal cancer cell proliferation by 
      competitively binding to Keap1 with TRIM25 via the USP17/Elk-1/CDK6 axis.
    findings: []
  - id: PMID:37187359
    title: Geniposide ameliorates dextran sulfate sodium-induced ulcerative 
      colitis via KEAP1-Nrf2 signaling pathway.
    findings: []
  - id: PMID:39009827
    title: Proteome-scale characterisation of motif-based interactome rewiring 
      by disease mutations.
    findings: []
  - id: PMID:40205054
    title: Multimodal cell maps as a foundation for structural and functional 
      genomics.
    findings: []
  - id: Reactome:R-HSA-6781764
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-8932327
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-8952630
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-8952631
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-8955241
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-8955289
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-8956040
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-9712274
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-9755505
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-9755507
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-9758090
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-9759169
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-9759172
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-9766645
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-9766656
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-9766677
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-9766687
    title: Reactome pathway annotation
    findings: []
  - id: Reactome:R-HSA-9796040
    title: Reactome pathway annotation
    findings: []
  - id: file:human/KEAP1/KEAP1-deep-research-falcon.md
    title: Deep research report on KEAP1
    findings: []
tags:
  - ferroptosis

KEAP1

Gene Description

Existing Annotations Review

Core Functions

KEAP1 functions as the substrate-recognition component (substrate adaptor) of the CUL3-RBX1 E3 ubiquitin ligase complex. It binds CUL3 via its BTB domain and recruits substrates (primarily NRF2) via its Kelch domain.

KEAP1 inhibits NRF2 (NFE2L2), a master transcription factor regulating antioxidant and cytoprotective gene expression. Under basal conditions, KEAP1 targets NRF2 for ubiquitination and proteasomal degradation, thereby inhibiting NRF2-mediated transcription.

References

Tags

📚 Additional Documentation

Deep Research Bioreason

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Bioreason Rl

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

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

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

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

Research Target:

Citations

Bioreason Rl Review

BioReason-Pro RL Review: KEAP1 (human)

Functional Summary Review

Notes on thinking trace

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