id: Q86Y37 gene_symbol: CACUL1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- CACUL1 (CDK2-associated and cullin domain-containing protein 1; also known as CAC1 / C10orf46) is a poorly characterized 369-amino-acid human protein containing a single cullin-repeat-like domain with disordered N- and C-terminal regions. Despite its name and cullin-fold homology, it is much shorter than canonical cullins (~750-900 aa) and there is no experimental evidence that it nucleates a functional cullin-RING ubiquitin ligase or carries a neddylation/RBX module. The best-supported activity, from a single study, is physical association with the cyclin-dependent kinase CDK2 and promotion of CDK2 kinase activity, consistent with a role in G1/S cell-cycle progression and proliferation; the protein is highly expressed in cancer tissues and cell lines, and its abundance varies across the cell cycle. CACUL1 also acts as a nuclear-receptor transcriptional corepressor: it is a SIRT1-interacting protein that binds PPARgamma (and estrogen receptor alpha) and represses their transcription by coordinating SIRT1 and the histone demethylase LSD1/KDM1A at target promoters (lowering H3K9 acetylation and raising H3K9 methylation), thereby suppressing adipocyte differentiation. Separately, although CACUL1 does not itself nucleate a cullin-RING ligase, it binds the Cul3-Keap1-Rbx1 (CRL3-Keap1) ubiquitin-ligase complex and attenuates its ubiquitination of the transcription factor Nrf2 (NFE2L2), stabilizing Nrf2 and promoting the antioxidant response. CACUL1 has also been recovered as a yeast two-hybrid interactor of ARMC5. Overall, CACUL1 is a multifunctional protein linking CDK2-associated cell-cycle progression, nuclear-receptor corepression, and negative regulation of Nrf2 ubiquitination. alternative_products: - name: '1' id: Q86Y37-1 - name: '2' id: Q86Y37-2 sequence_note: VSP_013936, VSP_013937 - name: '4' id: Q86Y37-4 sequence_note: VSP_013933 existing_annotations: - term: id: GO:0000082 label: G1/S transition of mitotic cell cycle evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: >- Phylogenetic (IBA) transfer of a G1/S cell-cycle role. This is consistent with the direct experimental evidence in the same gene (PMID:19829063), where CACUL1/CAC1 knockdown induces G1/S arrest. Retained but as a non-core/secondary process annotation since the defining molecular activity is the CDK2 interaction rather than the broader cell-cycle process itself. action: KEEP_AS_NON_CORE reason: >- Supported indirectly by direct knockdown evidence (PMID:19829063) that CACUL1 loss causes G1/S arrest, but this is a downstream process rather than a precise molecular function; treat as a non-core involvement. supported_by: - reference_id: PMID:19829063 supporting_text: >- Knockdown of CAC1 by RNAi inhibits cell proliferation and induces G(1)/S arrest. - term: id: GO:0019901 label: protein kinase binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: >- Phylogenetic (IBA) transfer of protein kinase binding. This is the same molecular function directly demonstrated for CACUL1 via its physical interaction with CDK2 (PMID:19829063). Accept as it reflects the best-supported molecular activity of the protein. action: ACCEPT reason: >- Directly corroborated by experimental CDK2 binding (PMID:19829063); the IBA call coincides with the strongest molecular evidence for this protein. supported_by: - reference_id: PMID:19829063 supporting_text: this protein is physically associated with CDK2 - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: >- The IEA InterPro2GO transfer (cullin-repeat domain IPR001373) implies direct participation in ubiquitin-dependent catabolism, which remains unsupported: CACUL1 is too short to be a CRL scaffold and carries no RBX/neddylation module. However, Kigoshi et al. 2015 (PMID:26238671) show CACUL1 binds the Cul3-Keap1-Rbx1 ubiquitin-ligase complex and ATTENUATES Nrf2 ubiquitination, stabilizing Nrf2. The experimentally supported role is therefore NEGATIVE regulation of (Nrf2) ubiquitination, not direct participation in catabolism; modify accordingly. action: MODIFY reason: >- Direct participation in ubiquitin-dependent catabolism is a domain-only over-annotation, but CACUL1 has experimentally demonstrated activity as a negative regulator of Nrf2 ubiquitination via the Cul3-Keap1-Rbx1 complex (PMID:26238671); replace with negative regulation of protein ubiquitination. proposed_replacement_terms: - id: GO:0031397 label: negative regulation of protein ubiquitination supported_by: - reference_id: PMID:26238671 supporting_text: CACUL1 attenuates Nrf2 ubiquitination - reference_id: PMID:26238671 supporting_text: CACUL1 stabilizes Nrf2 by regulating Nrf2 ubiquitination - term: id: GO:0031625 label: ubiquitin protein ligase binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: >- Although the IEA call was originally a pure cullin-domain (IPR001373) transfer, it is now experimentally supported: Kigoshi et al. 2015 (PMID:26238671) demonstrate that CACUL1 binds Keap1, Cul3 and Rbx1 - the components of the ubiquitin ligase (CRL3) responsible for Nrf2 ubiquitination - and thereby modulates that ligase's activity toward Nrf2. The ubiquitin-protein-ligase-binding molecular function is therefore retained with direct experimental support. action: ACCEPT reason: >- Experimentally demonstrated binding to the Cul3-Keap1-Rbx1 ubiquitin ligase complex (PMID:26238671) directly supports this molecular function; it is no longer a domain-only over-annotation. supported_by: - reference_id: PMID:26238671 supporting_text: >- we further assessed CACUL1 binding with Keap1, Cul3 and Rbx1, the components of the Ubiquitin ligase responsible for Nrf2 ubiquitination. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23178685 qualifier: enables review: summary: >- This IPI annotation (WITH ESR1/P03372) records the physical interaction between CACUL1/CAC1 and estrogen receptor alpha (ERalpha), corroborated by IntAct (NbExp=5). The bare "protein binding" term is uninformative; a more specific molecular function is warranted given the established, directional ERalpha interaction. action: MODIFY reason: >- The interaction partner is a specific nuclear receptor (ERalpha); replace the uninformative protein binding term with nuclear estrogen receptor binding to capture the actual molecular function. proposed_replacement_terms: - id: GO:0030331 label: nuclear estrogen receptor binding supported_by: - reference_id: PMID:23178685 supporting_text: >- The CoRNR box of CAC1 was required for the binding to and inactivation of ERα. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28169274 qualifier: enables review: summary: >- This IPI annotation (WITH ARMC5/Q96C12) derives from a yeast two-hybrid screen in which CACUL1 was one of 16 ARMC5-binding partners. The paper characterizes ARMC5, not CACUL1, and provides no functional context for CACUL1. The bare "protein binding" term is uninformative and rests on a single high-throughput Y2H datum. action: MARK_AS_OVER_ANNOTATED reason: >- Uninformative bare protein binding from a single Y2H hit in an ARMC5-focused study; no specific function or biology for CACUL1 is established. supported_by: - reference_id: PMID:28169274 supporting_text: Yeast 2-hybrid assays identify 16 ARMC5-binding partners. - term: id: GO:0000082 label: G1/S transition of mitotic cell cycle evidence_type: IMP original_reference_id: PMID:19829063 qualifier: involved_in review: summary: >- Direct experimental evidence: RNAi knockdown of CACUL1/CAC1 induces G1/S arrest, indicating involvement in the G1/S transition. This is a genuine process annotation but downstream of the protein's molecular role in activating CDK2; retained as a non-core involvement. action: KEEP_AS_NON_CORE reason: >- Well-supported by knockdown phenotype, but the broad cell-cycle process is secondary to the precise CDK2-activating molecular function. supported_by: - reference_id: PMID:19829063 supporting_text: >- Knockdown of CAC1 by RNAi inhibits cell proliferation and induces G(1)/S arrest. - term: id: GO:0008284 label: positive regulation of cell population proliferation evidence_type: IMP original_reference_id: PMID:19829063 qualifier: involved_in review: summary: >- Direct experimental evidence: CACUL1/CAC1 knockdown inhibits cell proliferation, supporting a positive role in proliferation. This is a real but downstream phenotypic process annotation; kept as non-core relative to the underlying CDK2-activating molecular function. action: KEEP_AS_NON_CORE reason: >- Supported by knockdown phenotype but is a broad downstream process rather than the precise molecular activity. supported_by: - reference_id: PMID:19829063 supporting_text: >- Knockdown of CAC1 by RNAi inhibits cell proliferation and induces G(1)/S arrest. - term: id: GO:0019901 label: protein kinase binding evidence_type: IPI original_reference_id: PMID:19829063 qualifier: enables review: summary: >- Direct experimental evidence (IPI, WITH CDK2/P24941) for physical association of CACUL1/CAC1 with the cyclin-dependent kinase CDK2. This is the best-supported molecular function of the protein and represents a core activity. action: ACCEPT reason: >- Directly demonstrated CDK2 binding; an informative molecular-function term reflecting the protein's defining characterized interaction. supported_by: - reference_id: PMID:19829063 supporting_text: this protein is physically associated with CDK2 - term: id: GO:0045860 label: positive regulation of protein kinase activity evidence_type: IMP original_reference_id: PMID:19829063 qualifier: involved_in review: summary: >- Direct experimental evidence that CACUL1/CAC1 promotes CDK2 kinase activity. This captures the functional consequence of the CDK2 interaction and is a core aspect of the protein's characterized activity, though the molecular mechanism of activation remains undefined. action: ACCEPT reason: >- Supported by experiments showing CAC1 promotes CDK2 kinase activity; a well-evidenced functional annotation. supported_by: - reference_id: PMID:19829063 supporting_text: >- CAC1 interacts with CDK2 and promotes the kinase activity of CDK2 protein - term: id: GO:0003714 label: transcription corepressor activity evidence_type: IDA original_reference_id: PMID:29233982 qualifier: enables review: summary: >- Proposed NEW molecular-function annotation (not in current GOA). CACUL1 represses PPARgamma- (PMID:29233982) and ERalpha- (PMID:23178685) dependent transcription by coordinating SIRT1 and LSD1 at target promoters, i.e. it acts as a nuclear-receptor transcription corepressor. This is the informative MF underlying the existing bare protein-binding / nuclear estrogen receptor binding annotations. action: NEW reason: >- Two independent studies show CACUL1 physically binds nuclear receptors (PPARgamma, ERalpha) and represses their transcriptional activity via SIRT1/LSD1; transcription corepressor activity captures this MF. supported_by: - reference_id: PMID:29233982 supporting_text: >- CACUL1, identified as a novel SIRT1 interacting protein, physically interacts with PPARγ and represses its transcriptional activity, suppressing adipocyte differentiation - reference_id: PMID:23178685 supporting_text: CAC1, associated with LSD1, functions as an ERα corepressor - term: id: GO:0042975 label: peroxisome proliferator activated receptor binding evidence_type: IPI original_reference_id: PMID:29233982 qualifier: enables review: summary: >- Proposed NEW molecular-function annotation (not in current GOA). CACUL1 physically interacts with PPARgamma, providing the receptor-binding basis for its corepressor activity at PPARgamma-responsive promoters. action: NEW reason: >- Direct physical interaction of CACUL1 with PPARgamma demonstrated (PMID:29233982); a specific, informative nuclear-receptor-binding MF. supported_by: - reference_id: PMID:29233982 supporting_text: >- CACUL1, identified as a novel SIRT1 interacting protein, physically interacts with PPARγ and represses its transcriptional activity, suppressing adipocyte differentiation - term: id: GO:0031397 label: negative regulation of protein ubiquitination evidence_type: IMP original_reference_id: PMID:26238671 qualifier: involved_in review: summary: >- Proposed NEW process annotation (not in current GOA), also offered as the MODIFY replacement for the domain-only GO:0006511 IEA. CACUL1 binds the Cul3-Keap1-Rbx1 complex and attenuates Nrf2 ubiquitination, stabilizing Nrf2 - a negative regulatory role in protein ubiquitination. action: NEW reason: >- Experimentally demonstrated attenuation of Nrf2 ubiquitination by CACUL1 (PMID:26238671) supports negative regulation of protein ubiquitination. supported_by: - reference_id: PMID:26238671 supporting_text: CACUL1 attenuates Nrf2 ubiquitination - reference_id: PMID:26238671 supporting_text: CACUL1 stabilizes Nrf2 by regulating Nrf2 ubiquitination - reference_id: file:human/CACUL1/CACUL1-deep-research-falcon.md supporting_text: >- CACUL1 associates with the Cul3-Keap1-Rbx1 ubiquitin ligase complex - term: id: GO:0050821 label: protein stabilization evidence_type: IMP original_reference_id: PMID:26238671 qualifier: involved_in review: summary: >- Proposed NEW process annotation (not in current GOA). By attenuating its ubiquitination, CACUL1 stabilizes the transcription factor Nrf2 (half-life ~10 -> ~30 min), the downstream consequence of its CRL3-Keap1 modulation. action: NEW reason: >- CACUL1 lengthens Nrf2 half-life by limiting its ubiquitination (PMID:26238671), consistent with a protein-stabilization role. supported_by: - reference_id: PMID:26238671 supporting_text: CACUL1 stabilizes Nrf2 by regulating Nrf2 ubiquitination core_functions: - description: >- Binds the cyclin-dependent kinase CDK2 and promotes its kinase activity, contributing to G1/S cell-cycle progression and cell proliferation. This is the best-characterized activity but rests on a single study and the molecular mechanism of CDK2 activation is undefined. molecular_function: id: GO:0019901 label: protein kinase binding directly_involved_in: - id: GO:0045860 label: positive regulation of protein kinase activity - id: GO:0000082 label: G1/S transition of mitotic cell cycle supported_by: - reference_id: PMID:19829063 supporting_text: >- CAC1 interacts with CDK2 and promotes the kinase activity of CDK2 protein - reference_id: PMID:19829063 supporting_text: this protein is physically associated with CDK2 - description: >- Acts as a context-dependent nuclear-receptor co-regulator: binds estrogen receptor alpha (ERalpha) via its CoRNR box and, in association with the histone demethylase LSD1/KDM1A, can repress ERalpha-dependent transcription. This is a secondary, less-established function reported by a single study. molecular_function: id: GO:0030331 label: nuclear estrogen receptor binding supported_by: - reference_id: PMID:23178685 supporting_text: >- The CoRNR box of CAC1 was required for the binding to and inactivation of ERα. - reference_id: PMID:23178685 supporting_text: CAC1, associated with LSD1, functions as an ERα corepressor - description: >- Functions as a nuclear-receptor transcriptional corepressor. CACUL1 is a SIRT1-interacting protein that also physically binds PPARgamma (and estrogen receptor alpha) and represses their transcriptional activity by reciprocally coordinating the histone deacetylase SIRT1 and the demethylase LSD1/KDM1A at target promoters, lowering H3K9 acetylation and raising H3K9 methylation; for PPARgamma this suppresses adipocyte differentiation. molecular_function: id: GO:0003714 label: transcription corepressor activity supported_by: - reference_id: PMID:29233982 supporting_text: >- CACUL1, identified as a novel SIRT1 interacting protein, physically interacts with PPARγ and represses its transcriptional activity, suppressing adipocyte differentiation - reference_id: PMID:29233982 supporting_text: >- CACUL1 functionally associates with SIRT1 and LSD1 at the PPARγ-responsive gene promoter, and regulates the level of histone H3K9 acetylation and methylation to repress PPARγ during adipocyte differentiation - reference_id: PMID:23178685 supporting_text: CAC1, associated with LSD1, functions as an ERα corepressor - description: >- Negatively regulates protein ubiquitination by binding the Cul3-Keap1-Rbx1 (CRL3-Keap1) ubiquitin-ligase complex and attenuating its ubiquitination of the transcription factor Nrf2 (NFE2L2), thereby stabilizing Nrf2 and sensitizing cells for the antioxidant/ARE response. This couples a cullin-RING-ligase-binding activity to a regulatory, rather than catalytic, role in the ubiquitin system. molecular_function: id: GO:0031625 label: ubiquitin protein ligase binding directly_involved_in: - id: GO:0031397 label: negative regulation of protein ubiquitination - id: GO:0050821 label: protein stabilization supported_by: - reference_id: PMID:26238671 supporting_text: >- we further assessed CACUL1 binding with Keap1, Cul3 and Rbx1, the components of the Ubiquitin ligase responsible for Nrf2 ubiquitination. - reference_id: PMID:26238671 supporting_text: CACUL1 attenuates Nrf2 ubiquitination knowledge_gaps: - gap_statement: >- The direct biochemical mechanism by which CACUL1 promotes CDK2 kinase activity remains unresolved: it is unclear whether CACUL1 allosterically activates CDK2, alters cyclin/CDK-inhibitor availability, changes substrate engagement, or acts through another cell-cycle regulatory complex. boundary: >- CACUL1 physically associates with CDK2, promotes CDK2 kinase activity, is expressed in a cell-cycle-dependent manner, and RNAi knockdown causes reduced proliferation with G1/S arrest. The unresolved part is the immediate molecular mechanism connecting CACUL1 binding to increased CDK2 activity. gap_kind: - BIOLOGY dark_aspect: RESIDUAL_SUBGAP status: OPEN significance: >- CDK2 regulation is the best-supported CACUL1 activity, but without a mechanism it is hard to distinguish a direct CDK2 co-regulator from an indirect cell-cycle phenotype. resolution: >- Reconstitute purified CACUL1-CDK2-cyclin complexes for kinase kinetics, map the binding interface, and test whether CACUL1 changes cyclin binding, CDK-inhibitor binding, or substrate phosphorylation in cells. provenance: - reference_id: PMID:19829063 supporting_text: >- but how CDK2 is regulated is still incompletely understood reference_section_type: ABSTRACT - reference_id: PMID:19829063 supporting_text: >- provide insight into the mechanism by which CDK2 is regulated reference_section_type: ABSTRACT - gap_statement: >- The role of CACUL1's cullin-repeat-like domain in CRL3-Keap1/Nrf2 regulation is unresolved, and CACUL1 should not be curated as a bona fide cullin-RING scaffold unless future experiments show that it assembles or positions an E3 ubiquitin ligase complex. boundary: >- CACUL1 binds Keap1, Cul3, and Rbx1 and attenuates Nrf2 ubiquitination, supporting ubiquitin-ligase binding and negative regulation of Nrf2 ubiquitination. The gap is whether the short cullin-like region is the binding/regulatory interface and whether CACUL1 modulates only CRL3-Keap1/Nrf2 or broader CRL3 substrate ubiquitination. gap_kind: - BIOLOGY - CURATION dark_aspect: RESIDUAL_SUBGAP status: OPEN significance: >- This boundary prevents domain-only over-propagation of cullin scaffold activity while preserving the experimentally supported CRL3-Keap1/Nrf2 regulatory role. resolution: >- Map CACUL1 deletion mutants against Keap1, Cul3, Rbx1, and Nrf2; assay CRL3 ubiquitination activity with purified components; and test whether CACUL1 affects other CRL3-Keap1 or Cul3 substrates. provenance: - reference_id: PMID:26238671 supporting_text: >- CACUL1 is a regulator of Nrf2 ubiquitination, adding another regulatory layer to the Nrf2 antioxidant stress response. reference_section_type: ABSTRACT - reference_id: file:human/CACUL1/CACUL1-pn-notes.md supporting_text: >- there is no experimental evidence that it nucleates a functional cullin-RING ubiquitin ligase or carries a neddylation/RBX module - gap_statement: >- The physiological context and directionality of CACUL1 nuclear-receptor coregulation remain only partly defined, especially whether ERalpha, androgen receptor, and PPARgamma effects represent one general chromatin mechanism or distinct receptor- and cell-type-specific activities. boundary: >- CACUL1 can bind nuclear receptors and repress ERalpha- and PPARgamma-dependent transcription with LSD1/SIRT1-linked chromatin changes. The unresolved part is which tissues and metabolic or hormonal states require this activity in vivo, and when CACUL1 acts as a corepressor versus a co-regulator with different directionality. gap_kind: - BIOLOGY dark_aspect: RESIDUAL_SUBGAP status: OPEN significance: >- Nuclear-receptor corepression is experimentally supported but may be highly context-dependent; resolving context will determine whether CACUL1 should be treated as a broadly relevant transcriptional regulator or a narrower adipocyte and hormone-response modulator. resolution: >- Combine receptor-specific ChIP-seq/CUT&RUN, transcriptomics, and CACUL1 loss- and gain-of-function in relevant adipocyte and hormone-responsive models, followed by in vivo perturbation where feasible. provenance: - reference_id: PMID:29233982 supporting_text: >- The physiological significance of CACUL1-mediated PPARγ repression under different dietary conditions is of potential interest. reference_section_type: DISCUSSION - reference_id: PMID:29233982 supporting_text: >- Therefore, adipogenesis may be fine-tuned by dynamic regulation of PPARγ in response to different dietary conditions. reference_section_type: DISCUSSION proposed_new_terms: [] suggested_questions: - question: >- Does CACUL1 act as a bona fide CDK2 regulator through a direct structural/allosteric mechanism, or indirectly via cyclin or CDK-inhibitor levels? - question: >- Is the nuclear-receptor co-regulatory activity of CACUL1 (ERalpha repression via LSD1, and the separately reported androgen-receptor co-regulation) physiologically significant, and how is its directionality (corepressor vs coactivator) determined? - question: >- CACUL1 binds the Cul3-Keap1-Rbx1 (CRL3) complex and negatively regulates Nrf2 ubiquitination (PMID:26238671) without nucleating its own ligase - does its cullin-repeat-like domain mediate this CRL3 association, and is the regulation Nrf2-specific or a more general modulation of CRL3-Keap1 substrate ubiquitination? suggested_experiments: - description: >- In vitro reconstituted CDK2 kinase assays with purified recombinant CACUL1 to test whether it directly stimulates CDK2 activity, and structural/biophysical mapping (e.g., cryo-EM or co-crystallization, HDX-MS) of the CACUL1-CDK2 interface. experiment_type: biochemical/structural hypothesis: >- CACUL1 directly binds and allosterically activates CDK2 independent of cyclin levels. - description: >- Affinity purification-mass spectrometry of endogenous CACUL1 across cell-cycle stages to define its stable interactome and test for any RBX/neddylation or cullin-RING ligase components. experiment_type: proteomics hypothesis: >- CACUL1 does not assemble a canonical cullin-RING ligase and instead functions through CDK2 and nuclear-receptor/chromatin partners. - description: >- ChIP-seq and reporter assays for CACUL1 at ERalpha- and androgen-receptor- responsive promoters with and without LSD1, to define its co-regulatory direction and chromatin effects. experiment_type: genomics/transcription hypothesis: >- CACUL1 modulates nuclear-receptor target genes through LSD1-dependent changes in histone methylation. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: PMID:19829063 title: Identification and characterization of CAC1 as a novel CDK2-associated cullin. findings: - statement: >- CACUL1/CAC1 is a 369-aa cullin-domain protein that physically associates with CDK2, promotes CDK2 kinase activity, and is required for G1/S progression and proliferation; highly expressed in cancers. supporting_text: >- CAC1 interacts with CDK2 and promotes the kinase activity of CDK2 protein, we propose that CAC1 is a novel cell cycle associated protein capable of promoting cell proliferation. - id: PMID:23178685 title: Negative regulation of ERα by a novel protein CAC1 through association with histone demethylase LSD1. findings: - statement: >- CAC1 binds ERalpha via its CoRNR box and, in association with LSD1, functions as an ERalpha corepressor, increasing H3K9me3 at ERalpha target promoters. supporting_text: >- CAC1, associated with LSD1, functions as an ERα corepressor, implicating a potential antitumor target in ERα-positive breast cancer. - id: PMID:28169274 title: Armc5 deletion causes developmental defects and compromises T-cell immune responses. findings: - statement: >- CACUL1 was recovered as one of 16 ARMC5-binding partners in a yeast two-hybrid screen; the study characterizes ARMC5, not CACUL1. supporting_text: Yeast 2-hybrid assays identify 16 ARMC5-binding partners. - id: PMID:26238671 title: CACUL1/CAC1 Regulates the Antioxidant Response by Stabilizing Nrf2. findings: - statement: >- CACUL1 binds the Cul3-Keap1-Rbx1 ubiquitin-ligase complex and attenuates Nrf2 ubiquitination, stabilizing Nrf2 (half-life ~10 -> ~30 min) and sensitizing cells for the antioxidant (ARE) response; CACUL1 is itself oxidative-stress-induced. supporting_text: >- we further assessed CACUL1 binding with Keap1, Cul3 and Rbx1, the components of the Ubiquitin ligase responsible for Nrf2 ubiquitination. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PMID resolved from DOI 10.1038/srep12857 via NCBI and the cached title matches; supporting_text quotes are verbatim from the cached full text. Provides experimental support that upgrades the previously domain-only ubiquitin-ligase-binding (GO:0031625) and reframes the ubiquitin-catabolism IEA as negative regulation of ubiquitination (GO:0031397). - id: PMID:29233982 title: CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARγ and inhibit adipogenesis. findings: - statement: >- CACUL1 is a SIRT1-interacting protein that physically binds PPARgamma and represses its transcriptional activity by coordinating SIRT1 and LSD1 at target promoters (altering H3K9 acetylation/methylation), suppressing adipocyte differentiation. supporting_text: >- CACUL1, identified as a novel SIRT1 interacting protein, physically interacts with PPARγ and represses its transcriptional activity, suppressing adipocyte differentiation reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PMID resolved from DOI 10.1038/s41419-017-0070-z via NCBI and the cached title matches; supporting_text quotes are verbatim from the cached full text. Establishes a SIRT1/LSD1-coupled nuclear-receptor (PPARgamma) transcription-corepressor activity, broadening the ERalpha co-regulator report.