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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | 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. 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). Supporting Evidence: PMID:15572695 Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. file:human/KEAP1/KEAP1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: KEAP1 is predominantly localized in the cytoplasm where it sequesters NRF2 and targets it for degradation (PMID:15601839, UniProt Q14145). 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). Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: KEAP1 functions as a substrate adaptor protein for the CUL3-dependent E3 ubiquitin ligase complex, recruiting NRF2 for ubiquitination (PMID:15572695, PMID:15601839). 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). Supporting Evidence: PMID:15572695 Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IBA GO_REF:0000033 | ACCEPT | 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). 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." Supporting Evidence: PMID:15572695 Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. PMID:15983046 2005 Jun 27. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: KEAP1 has been detected in the nucleus in some studies, though it is predominantly cytoplasmic. UniProt reports nuclear localization based on PMID:15657435. 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. Supporting Evidence: UniProt:Q14145 |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: KEAP1 is primarily cytoplasmic, where it functions to sequester and target NRF2 for degradation. Reason: Cytoplasmic localization is the established primary location for KEAP1 function. This is consistent with the IBA annotation and experimental evidence. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: High-throughput protein-protein interaction study. The specific interactor is ETF1 (eukaryotic translation termination factor 1). 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. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network. |
| GO:0005515 protein binding | IPI PMID:16888629 Structure of the Keap1:Nrf2 interface provides mechanistic i... | MODIFY | Summary: Structural study demonstrating the KEAP1-NRF2 interaction interface. The interactor is NRF2 (NFE2L2, Q16236). Reason: While this demonstrates a real and important interaction with NRF2, "protein binding" is uninformative. A more specific term should be used. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:16888629 Aug 3. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. |
| GO:0005515 protein binding | IPI PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, ... | MODIFY | Summary: Study demonstrating KEAP1 interaction with NRF2 and the role of DJ-1 in this interaction. The interactor is NRF2 (Q16236). Reason: This represents the functionally important KEAP1-NRF2 interaction. Should be annotated with a more specific term reflecting the regulatory relationship. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. |
| GO:0005515 protein binding | IPI PMID:17510365 Wilms tumor suppressor WTX negatively regulates WNT/beta-cat... | MARK AS OVER ANNOTATED | Summary: Study on WTX (AMER1) interaction. WTX interacts with multiple proteins including KEAP1. Reason: Generic protein binding annotation. The functional significance of KEAP1-AMER1/WTX interaction is not related to KEAP1's core function. Supporting Evidence: PMID:17510365 Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling. |
| GO:0005515 protein binding | IPI PMID:18757741 Cancer related mutations in NRF2 impair its recognition by K... | MODIFY | Summary: Study on cancer-related NRF2 mutations that impair KEAP1 recognition. Interactor is NRF2 (Q16236). Reason: Demonstrates the critical KEAP1-NRF2 interaction and how cancer mutations disrupt it. Should use more specific term. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:18757741 Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. |
| GO:0005515 protein binding | IPI PMID:19615732 Defining the human deubiquitinating enzyme interaction lands... | MARK AS OVER ANNOTATED | Summary: Deubiquitinating enzyme interaction landscape study. Multiple interactors identified including ETF1, MAD2L1, SQSTM1, DPP3, and others. Reason: High-throughput interaction study. Generic protein binding is uninformative for these various interactors. Supporting Evidence: PMID:19615732 Jul 16. Defining the human deubiquitinating enzyme interaction landscape. |
| GO:0005515 protein binding | IPI PMID:19706542 Nitric oxide activation of Keap1/Nrf2 signaling in human col... | MODIFY | Summary: Study on nitric oxide activation of KEAP1/NRF2 signaling. Interactor is NRF2. Reason: Represents KEAP1-NRF2 core regulatory interaction. Should use more specific term. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:19706542 Nitric oxide activation of Keap1/Nrf2 signaling in human colon carcinoma cells. |
| GO:0005515 protein binding | IPI PMID:20173742 The selective autophagy substrate p62 activates the stress r... | ACCEPT | Summary: Study on p62/SQSTM1 activation of NRF2 through KEAP1 inactivation. Interactors include SQSTM1. Reason: SQSTM1/p62 interaction with KEAP1 is functionally important for autophagy- mediated regulation of the KEAP1-NRF2 pathway. This is well-established. Supporting Evidence: PMID:20452972 2010 May 7. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. PMID:20173742 The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. |
| GO:0005515 protein binding | IPI PMID:20452972 p62/SQSTM1 is a target gene for transcription factor NRF2 an... | ACCEPT | Summary: Detailed study on p62/SQSTM1-KEAP1 interaction and its role in autophagy- mediated NRF2 activation. Interactor is SQSTM1 (Q13501). Reason: The SQSTM1-KEAP1 interaction is functionally important and represents a key regulatory mechanism linking autophagy to oxidative stress response. Well characterized interaction. Supporting Evidence: PMID:20452972 2010 May 7. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | ACCEPT | Summary: Network organization of autophagy system study. Interactor is SQSTM1. Reason: SQSTM1/p62-KEAP1 interaction is a genuine and functionally relevant interaction for autophagy regulation. Supporting Evidence: PMID:20562859 Network organization of the human autophagy system. |
| GO:0005515 protein binding | IPI PMID:20600852 Suppression of NF-kappaB signaling by KEAP1 regulation of IK... | KEEP AS NON CORE | Summary: Study on KEAP1 suppression of NF-kappaB signaling via IKKbeta regulation. Interactors include IKBKB. Reason: KEAP1-IKKbeta interaction may represent a secondary function related to NF-kappaB regulation, but this is not the primary function of KEAP1. Supporting Evidence: PMID:20600852 2010 Jun 20. Suppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta activity through autophagic degradation and inhibition of phosphorylation. |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | MARK AS OVER ANNOTATED | Summary: Telomere signaling study. Interactor is TERF1. Reason: The functional significance of KEAP1-TERF1 interaction is unclear and not related to KEAP1's established functions. Supporting Evidence: PMID:21044950 Epub 2010 Nov 2. Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells. |
| GO:0005515 protein binding | IPI PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by... | ACCEPT | Summary: Cullin-RING ubiquitin ligase network study. Interactor is CUL3 (Q13618). Reason: CUL3 is the scaffold protein that KEAP1 binds to form the BCR(KEAP1) E3 ligase complex. This is a core functional interaction. Supporting Evidence: PMID:15572695 Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | MARK AS OVER ANNOTATED | Summary: Next-generation sequencing interactome study. Interactor is DPP3. Reason: High-throughput study. The DPP3-KEAP1 interaction significance is unclear. Supporting Evidence: PMID:21516116 Next-generation sequencing to generate interactome datasets. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | MARK AS OVER ANNOTATED | Summary: Innate immunity interaction network study. Interactor is IRF1. Reason: High-throughput study; functional significance unclear for KEAP1 core function. Supporting Evidence: PMID:21903422 2011 Sep 8. Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | ACCEPT | Summary: Human liver protein interaction network study. Multiple interactors including NRF2, NFE2L1, and others. Reason: Includes the important NRF2 interaction which is core to KEAP1 function. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver. |
| GO:0005515 protein binding | IPI PMID:23274085 Sestrins activate Nrf2 by promoting p62-dependent autophagic... | ACCEPT | Summary: Study on Sestrins activating NRF2 by promoting p62-dependent autophagic degradation of KEAP1. Interactor is SESN2 (P58004). Reason: SESN2-KEAP1 interaction is functionally relevant for autophagy-mediated regulation of KEAP1-NRF2 signaling. Supporting Evidence: PMID:23274085 Dec 27. Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Large-scale human interactome mapping. Multiple interactors identified. Reason: High-throughput study with many interactors; generic protein binding is uninformative. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:25684205 CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP ... | MODIFY | Summary: Study on CUL3-KBTBD6/7 ubiquitin ligase. Interactor is NRF2. Reason: NRF2 interaction should use more specific term. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:25684205 2015 Feb 12. CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP proteins to spatially restrict TIAM1-RAC1 signaling. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | ACCEPT | Summary: Study on genetic disorder-associated interaction perturbations. Multiple interactors including SQSTM1. Reason: Includes SQSTM1 interaction which is functionally important. Supporting Evidence: PMID:25910212 Widespread macromolecular interaction perturbations in human genetic disorders. |
| GO:0005515 protein binding | IPI PMID:27107014 An inter-species protein-protein interaction network across ... | MARK AS OVER ANNOTATED | Summary: Inter-species protein interaction network study. Reason: High-throughput cross-species study; generic annotation. Supporting Evidence: PMID:27107014 An inter-species protein-protein interaction network across vast evolutionary distance. |
| GO:0005515 protein binding | IPI PMID:29792731 APR3 modulates oxidative stress and mitochondrial function i... | MODIFY | Summary: APR3 modulation of oxidative stress. Interactor is NRF2. Reason: NRF2 interaction should use more specific term. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:29792731 of print. APR3 modulates oxidative stress and mitochondrial function in ARPE-19 cells. |
| GO:0005515 protein binding | IPI PMID:30190310 Dimerization quality control ensures neuronal development an... | ACCEPT | Summary: Dimerization quality control study. Interactor is KLHL2 (O95198). Reason: KLHL2 is a related BTB-Kelch family member; interaction may reflect heterodimerization potential. Supporting Evidence: PMID:30190310 2018 Sep 6. Dimerization quality control ensures neuronal development and survival. |
| GO:0005515 protein binding | IPI PMID:31169361 A Case Study on the Keap1 Interaction with Peptide Sequence ... | MARK AS OVER ANNOTATED | Summary: Peptidomic study on KEAP1 peptide epitope interactions. Multiple interactors. Reason: Methodological study on peptide binding; generic annotation. Supporting Evidence: PMID:31169361 2019 Jun 6. A Case Study on the Keap1 Interaction with Peptide Sequence Epitopes Selected by the Peptidomic mRNA Display. |
| GO:0005515 protein binding | IPI PMID:31262713 FAM129B, an antioxidative protein, reduces chemosensitivity ... | ACCEPT | Summary: Study on FAM129B/NIBAN2 competing with NRF2 for KEAP1 binding. Interactors include NRF2 and NIBAN2. Reason: NIBAN2 competition for KEAP1 binding represents a regulatory mechanism for NRF2 activation. Supporting Evidence: PMID:31262713 Jun 28. FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 binding. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: Study on genetic variant effects on protein interactions. Reason: High-throughput variant study; generic annotation. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Reference human binary protein interactome map. Many interactors identified. Reason: Large-scale interactome study; generic protein binding is uninformative. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Neurodegenerative disease protein interactome study. Reason: High-throughput study; generic annotation. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005515 protein binding | IPI PMID:32911434 A functionally defined high-density NRF2 interactome reveals... | MODIFY | Summary: High-density NRF2 interactome study. Interactor is NRF2 (Q16236). Reason: NRF2 interaction should use more specific term. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:32911434 Aug 20. A functionally defined high-density NRF2 interactome reveals new conditional regulators of ARE transactivation. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Dual proteome-scale interactome network study. Reason: Large-scale interactome study; generic annotation. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:34591612 A protein interaction landscape of breast cancer. | MARK AS OVER ANNOTATED | Summary: Breast cancer protein interaction landscape study. Reason: High-throughput cancer interactome study; generic annotation. Supporting Evidence: PMID:34591612 Oct 1. A protein interaction landscape of breast cancer. |
| GO:0005515 protein binding | IPI PMID:34591642 A protein network map of head and neck cancer reveals PIK3CA... | MARK AS OVER ANNOTATED | Summary: Head and neck cancer protein network study. Reason: High-throughput cancer interactome study; generic annotation. Supporting Evidence: PMID:34591642 Oct 1. A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity. |
| GO:0005515 protein binding | IPI PMID:35044719 Proteome-scale mapping of binding sites in the unstructured ... | MARK AS OVER ANNOTATED | Summary: Proteome-scale binding site mapping in unstructured regions. Reason: High-throughput binding study; generic annotation. Supporting Evidence: PMID:35044719 Proteome-scale mapping of binding sites in the unstructured regions of the human proteome. |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | MARK AS OVER ANNOTATED | Summary: Cancer mutation-directed neo-interaction discovery. Interactors include BRAF and NRF2. Reason: High-throughput study; generic annotation. Supporting Evidence: PMID:35512704 2022 May 4. Systematic discovery of mutation-directed neo-protein-protein interactions in cancer. |
| GO:0005515 protein binding | IPI PMID:37187359 Geniposide ameliorates dextran sulfate sodium-induced ulcera... | MODIFY | Summary: Geniposide effects on KEAP1-NRF2 signaling in colitis. Interactor is NRF2. Reason: NRF2 interaction should use more specific term. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:37187359 2023 May 13. Geniposide ameliorates dextran sulfate sodium-induced ulcerative colitis via KEAP1-Nrf2 signaling pathway. |
| GO:0005515 protein binding | IPI PMID:39009827 Proteome-scale characterisation of motif-based interactome r... | MARK AS OVER ANNOTATED | Summary: Proteome-scale motif-based interaction rewiring by disease mutations. Reason: High-throughput study; generic annotation. Supporting Evidence: PMID:39009827 2024 Jul 15. Proteome-scale characterisation of motif-based interactome rewiring by disease mutations. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Multimodal cell maps study. Reason: High-throughput structural/functional genomics study; generic annotation. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred from mouse ortholog. Some KEAP1 may localize to ER, possibly related to interaction with NFE2L1 which has ER localization. Reason: KEAP1 is primarily cytoplasmic but may have minor ER localization related to NFE2L1 regulation. Not a primary localization. |
| GO:0005884 actin filament | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred from mouse ortholog. KEAP1 may associate with actin cytoskeleton. Reason: KEAP1 has been reported to associate with the actin cytoskeleton, but this is not its primary localization. |
| GO:0006511 ubiquitin-dependent protein catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: KEAP1 participates in ubiquitin-dependent protein catabolism by targeting NRF2 for ubiquitination. Reason: This is a core function of KEAP1. The more specific term GO:0043161 (proteasome-mediated) is also annotated. |
| GO:0010506 regulation of autophagy | IEA GO_REF:0000107 | ACCEPT | Summary: KEAP1 is involved in autophagy regulation through its interaction with SQSTM1/p62 (PMID:20452972). Reason: KEAP1 is regulated by and participates in autophagy through SQSTM1/p62 interaction, which sequesters KEAP1 in inclusion bodies. Supporting Evidence: PMID:20452972 2010 May 7. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. |
| GO:0016234 inclusion body | IEA GO_REF:0000107 | ACCEPT | Summary: KEAP1 localizes to inclusion bodies through interaction with SQSTM1/p62 during selective autophagy. Reason: KEAP1 relocalizes to p62/SQSTM1-positive inclusion bodies during autophagy activation (PMID:20452972). Supporting Evidence: PMID:20452972 2010 May 7. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000120 | ACCEPT | Summary: KEAP1 is involved in protein ubiquitination as the substrate adaptor for the CRL3 complex. Reason: This is a core function of KEAP1, which targets NRF2 (and other substrates) for ubiquitination. |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IEA GO_REF:0000107 | ACCEPT | Summary: KEAP1 is a component of the CUL3-RING ubiquitin ligase complex. Reason: Duplicate of IBA annotation. KEAP1 is established as part of the CRL3 complex. |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: KEAP1 is part of protein complexes including the BCR(KEAP1) E3 ligase complex. Reason: This is an overly generic term. More specific terms like GO:0031463 (Cul3-RING ubiquitin ligase complex) are already annotated. |
| GO:0034599 cellular response to oxidative stress | IEA GO_REF:0000107 | ACCEPT | Summary: KEAP1 is the key sensor and regulator of cellular response to oxidative stress through NRF2 regulation. 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. Supporting Evidence: PMID:15572695 Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: KEAP1 homodimerizes via its BTB domain to form the functional substrate adaptor for the CRL3 complex. Reason: KEAP1 homodimerization is essential for its function. The BCR(KEAP1) complex contains 2 molecules of KEAP1 (UniProt). Supporting Evidence: UniProt:Q14145 |
| GO:0097718 disordered domain specific binding | IEA GO_REF:0000107 | ACCEPT | Summary: KEAP1's Kelch domain binds the intrinsically disordered Neh2 domain of NRF2 via ETGE and DLG motifs. Reason: KEAP1 binds the disordered Neh2 domain of NRF2, which contains the ETGE and DLG degron motifs. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Human Protein Atlas immunofluorescence data indicates some KEAP1 in nucleoplasm. Reason: KEAP1 is primarily cytoplasmic but may have minor nuclear localization. This is not the primary site of function. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence confirms cytosolic localization of KEAP1. Reason: Cytosolic localization is well established for KEAP1. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:29249570 Cullin 3-Based Ubiquitin Ligases as Master Regulators of Mam... | ACCEPT | Summary: Review on CUL3-based ubiquitin ligases confirms KEAP1's role in proteasomal degradation of substrates. Reason: This is a core function of KEAP1. Well-established that KEAP1 targets NRF2 for proteasomal degradation. Supporting Evidence: PMID:29249570 Epub 2017 Dec 14. Cullin 3-Based Ubiquitin Ligases as Master Regulators of Mammalian Cell Differentiation. |
| GO:0006511 ubiquitin-dependent protein catabolic process | IDA PMID:15572695 Keap1 is a redox-regulated substrate adaptor protein for a C... | ACCEPT | Summary: Study demonstrating KEAP1 functions as substrate adaptor for CUL3-dependent ubiquitin ligase targeting NRF2 for degradation (PMID:15572695). Reason: Core function of KEAP1 directly demonstrated. Supporting Evidence: PMID:15572695 Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:15572695 Keap1 is a redox-regulated substrate adaptor protein for a C... | ACCEPT | Summary: Directly demonstrates KEAP1 as substrate adaptor for CUL3-RBX1 E3 ligase (PMID:15572695). Reason: Core molecular function directly demonstrated. Supporting Evidence: PMID:15572695 Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. |
| GO:0005515 protein binding | IPI PMID:36882524 C4orf19 inhibits colorectal cancer cell proliferation by com... | ACCEPT | Summary: Study on C4orf19/PGCKA1 competing with TRIM25 for KEAP1 binding. Interactor is PGCKA1 (Q8IY42). Reason: PGCKA1 interaction with KEAP1 is functionally relevant for KEAP1 stability regulation. Supporting Evidence: PMID:36882524 2023 Mar 7. C4orf19 inhibits colorectal cancer cell proliferation by competitively binding to Keap1 with TRIM25 via the USP17/Elk-1/CDK6 axis. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | ACCEPT | Summary: Study demonstrating KEAP1 targets NRF2 for proteasomal degradation via CUL3-ROC1 ligase (PMID:15601839). Reason: Core function directly demonstrated. Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | ACCEPT | Summary: Study demonstrating KEAP1 functions as substrate adaptor (PMID:15601839). Reason: Core function directly demonstrated. Duplicate evidence with PMID:15572695. Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, ... | ACCEPT | Summary: Study showing KEAP1 negatively regulates NRF2 transcriptional activity (PMID:17015834). Reason: KEAP1 negatively regulates NRF2, a transcription factor that activates Pol II-dependent genes. This is achieved through degradation of NRF2. Supporting Evidence: PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. |
| GO:0140416 transcription regulator inhibitor activity | IDA PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, ... | ACCEPT | Summary: KEAP1 inhibits NRF2 transcription factor activity by promoting its degradation (PMID:17015834). Reason: Core function of KEAP1 as an inhibitor of NRF2 transcriptional activity. Supporting Evidence: PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. |
| GO:1902883 negative regulation of response to oxidative stress | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | ACCEPT | Summary: KEAP1 negatively regulates oxidative stress response by targeting NRF2 for degradation under basal conditions (PMID:15601839). Reason: Core function of KEAP1 - it suppresses the cellular antioxidant response by degrading NRF2 under normal conditions. Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9766645 | ACCEPT | Summary: Reactome pathway annotation for KEAP1 cytosolic localization. Reason: Cytosolic localization is well established. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9766656 | ACCEPT | Summary: Reactome pathway annotation for KEAP1 cytosolic localization. Reason: Duplicate cytosol annotation from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9766677 | ACCEPT | Summary: Reactome pathway annotation for KEAP1 cytosolic localization. Reason: Duplicate cytosol annotation from Reactome. |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, ... | ACCEPT | Summary: KEAP1 binds NRF2, an RNA Pol II-specific transcription factor, to regulate its stability and activity (PMID:17015834). Reason: This appropriately captures KEAP1's interaction with NRF2 (a transcription factor) more specifically than generic protein binding. Supporting Evidence: PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. |
| GO:0005515 protein binding | IPI PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | MODIFY | Summary: Demonstrates KEAP1 interaction with NRF2 (Q16236). Reason: Should use more specific term for NRF2 interaction. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0005737 cytoplasm | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | ACCEPT | Summary: Study demonstrates cytoplasmic localization of KEAP1 (PMID:15601839). Reason: Core localization directly demonstrated. Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0006511 ubiquitin-dependent protein catabolic process | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | ACCEPT | Summary: Study demonstrates KEAP1 role in ubiquitin-dependent degradation (PMID:15601839). Reason: Duplicate of earlier annotation; core function. Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0010506 regulation of autophagy | IDA PMID:20452972 p62/SQSTM1 is a target gene for transcription factor NRF2 an... | ACCEPT | Summary: Study demonstrates KEAP1 involvement in autophagy regulation through SQSTM1/p62 interaction (PMID:20452972). Reason: Well-characterized function of KEAP1 in autophagy regulation. Supporting Evidence: PMID:20452972 2010 May 7. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. |
| GO:0016234 inclusion body | IDA PMID:20452972 p62/SQSTM1 is a target gene for transcription factor NRF2 an... | ACCEPT | Summary: KEAP1 accumulates in p62-positive inclusion bodies during autophagy (PMID:20452972). Reason: Directly demonstrated localization during autophagy activation. Supporting Evidence: PMID:20452972 2010 May 7. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. |
| GO:0016567 protein ubiquitination | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | ACCEPT | Summary: KEAP1 promotes NRF2 ubiquitination (PMID:15601839). Reason: Core function directly demonstrated. Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | ACCEPT | Summary: Study identifies KEAP1 as component of CUL3-ROC1 complex (PMID:15601839). Reason: Core complex membership directly demonstrated. Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0034599 cellular response to oxidative stress | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | ACCEPT | Summary: KEAP1 regulates cellular response to oxidative stress by controlling NRF2 levels (PMID:15601839). Reason: Core function directly demonstrated. Supporting Evidence: PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |
| GO:0005515 protein binding | IPI PMID:26517842 Client Proteins and Small Molecule Inhibitors Display Distin... | KEEP AS NON CORE | Summary: Study on HSP90 isoform binding preferences. Interactors include HSP90AA1 (P07900) and HSP90AB1 (P08238). Reason: HSP90 interaction may represent chaperone-related regulation but is not core to KEAP1 function. Supporting Evidence: PMID:26517842 eCollection 2015. Client Proteins and Small Molecule Inhibitors Display Distinct Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and Their Conformationally Restricted Mutants. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6781764 | ACCEPT | Summary: Reactome pathway annotation. Reason: Cytosol localization is established. |
| GO:0005829 cytosol | TAS PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, ... | ACCEPT | Summary: Study supports cytosolic localization of KEAP1. Reason: Consistent with other evidence. Supporting Evidence: PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | TAS PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, ... | ACCEPT | Summary: KEAP1 promotes proteasomal degradation of NRF2 (PMID:17015834). Reason: Core function of KEAP1 as a positive regulator of NRF2 proteasomal degradation. Supporting Evidence: PMID:17015834 DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. |
| GO:0005515 protein binding | IPI PMID:24089205 Autophagy promotes primary ciliogenesis by removing OFD1 fro... | KEEP AS NON CORE | Summary: Study on autophagy and primary ciliogenesis. Interactor is OFD1 (Q9GZQ8) indirectly via MAP1LC3B. Reason: MAP1LC3B/LC3 interaction is relevant to autophagy regulation but not core to KEAP1's primary NRF2-regulatory function. Supporting Evidence: PMID:24089205 Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites. |
| GO:0005515 protein binding | IPI PMID:19424503 Ectodermal-neural cortex 1 down-regulates Nrf2 at the transl... | KEEP AS NON CORE | Summary: Study on ENC1/Ectodermal-neural cortex 1 regulation of NRF2. Interactor is ENC1 (O14682). Reason: ENC1 interaction with KEAP1 may modulate NRF2 regulation but is not the core interaction. Supporting Evidence: PMID:19424503 Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level. |
| GO:0005737 cytoplasm | IDA PMID:19424503 Ectodermal-neural cortex 1 down-regulates Nrf2 at the transl... | ACCEPT | Summary: Study confirms cytoplasmic localization. Reason: Additional evidence for cytoplasmic localization. Supporting Evidence: PMID:19424503 Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level. |
| GO:0016567 protein ubiquitination | IDA PMID:15983046 Ubiquitination of Keap1, a BTB-Kelch substrate adaptor prote... | ACCEPT | Summary: Study on KEAP1 ubiquitination and its role in the ubiquitin ligase complex (PMID:15983046). Reason: Core function directly demonstrated. Supporting Evidence: PMID:15983046 2005 Jun 27. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:15983046 Ubiquitination of Keap1, a BTB-Kelch substrate adaptor prote... | ACCEPT | Summary: Study confirms KEAP1 as component of CUL3-dependent complex (PMID:15983046). Reason: Core complex membership confirmed. Supporting Evidence: PMID:15983046 2005 Jun 27. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. |
| GO:0030496 midbody | IDA PMID:15166316 Dissection of the mammalian midbody proteome reveals conserv... | KEEP AS NON CORE | Summary: Midbody proteome study identified KEAP1 among midbody proteins (PMID:15166316). 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. Supporting Evidence: PMID:15166316 May 27. Dissection of the mammalian midbody proteome reveals conserved cytokinesis mechanisms. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8932327 | ACCEPT | Summary: Reactome pathway annotation for cytosol localization. Reason: Consistent with established cytosolic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952630 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952631 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9712274 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9755505 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9755507 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9758090 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9759169 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9759172 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9766687 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9796040 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with established localization. |
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