id: Q9C0C7 gene_symbol: AMBRA1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: AMBRA1 encodes a WD40-repeat scaffold and substrate-recognition component of CRL4/DDB1-CUL4 E3 ubiquitin ligase complexes. It regulates macroautophagy by linking ULK1 signaling to BECN1-PIK3C3 autophagosome nucleation, contributes to mitophagy through PRKN-, LC3/GABARAP-, and HUWE1-associated mechanisms, and acts as a CRL4 adaptor that promotes ubiquitin-dependent degradation of substrates such as D-type cyclins and ELOC. AMBRA1 also has context-specific roles in PP2A-dependent MYC and FOXO3 regulation, nuclear transcriptional scaffolding, immune-cell differentiation, and neural development. alternative_products: - name: '1' id: Q9C0C7-1 - name: '2' id: Q9C0C7-2 sequence_note: VSP_030657 - name: '3' id: Q9C0C7-3 sequence_note: VSP_030655 - name: '4' id: Q9C0C7-4 sequence_note: VSP_030654 - name: '5' id: Q9C0C7-5 sequence_note: VSP_030654, VSP_030656 - name: '6' id: Q9C0C7-6 sequence_note: VSP_030654, VSP_030655, VSP_045989, VSP_045990 existing_annotations: - term: id: GO:0000045 label: autophagosome assembly evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: AMBRA1 has direct evidence for promoting autophagosome assembly/nucleation. action: ACCEPT reason: AMBRA1 links ULK1 signaling, dynein release, and BECN1-PIK3C3 relocalization during autophagosome nucleation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0000423 label: mitophagy evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: AMBRA1 has direct evidence for roles in mitophagy. action: ACCEPT reason: Parkin-associated, LC3/GABARAP-associated, and HUWE1-associated evidence supports AMBRA1 involvement in mitochondrial clearance. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. - term: id: GO:0080008 label: Cul4-RING E3 ubiquitin ligase complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: AMBRA1 is a CRL4/DDB1-CUL4 substrate receptor/adaptor. action: ACCEPT reason: CRL4AMBRA1 evidence supports AMBRA1 as part of a Cul4-RING E3 ligase complex. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Multiple 2021 studies identify CRL4AMBRA1 as a cyclin D E3 ligase adaptor controlling G1/S progression through ubiquitin-dependent proteasomal degradation of D-type cyclins - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: AMBRA1 has core CRL4 substrate-adaptor activity. action: ACCEPT reason: Direct CRL4AMBRA1 studies support AMBRA1 as the substrate-recognition/adaptor component for ELOC and D-type cyclin ubiquitination. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: The PN projection contains an exact existing GOA match for `GO:1990756 ubiquitin-like ligase-substrate adaptor activity` through the UPS CRL4 substrate receptor branch. - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Nuclear localization is supported by AMBRA1 nuclear scaffolding studies. action: ACCEPT reason: Human AMBRA1 localizes to the nucleus in cancer cells and scaffolds transcriptional complexes at chromatin. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 has reported nuclear scaffolding roles in cancer cells - term: id: GO:0005739 label: mitochondrion evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Mitochondrial localization is supported in AMBRA1 mitophagy/autophagy studies. action: ACCEPT reason: AMBRA1 interacts with mitochondrial BCL2, Parkin-associated depolarized mitochondria, and LC3-dependent mitophagy machinery. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - term: id: GO:0005776 label: autophagosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Autophagosome localization is consistent with AMBRA1 autophagy and mitophagy roles. action: ACCEPT reason: AMBRA1 binds LC3 during mitophagy and acts at autophagosome nucleation steps. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Endoplasmic reticulum localization is supported during autophagosome nucleation. action: ACCEPT reason: After autophagy induction, AMBRA1 relocalization to the ER enables autophagosome nucleation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Cytosol localization is supported by Reactome and AMBRA1 autophagy/mitophagy evidence. action: ACCEPT reason: Cytosolic AMBRA1 complexes with dynein light chains and BECN1 are central to autophagy initiation models. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0005856 label: cytoskeleton evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Cytoskeleton localization/activity is supported by AMBRA1 dynein complex tethering. action: ACCEPT reason: The BECN1-VPS34 complex is tethered to the cytoskeleton through AMBRA1 and dynein light chains. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0005925 label: focal adhesion evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Focal adhesion localization is plausible but peripheral to the core AMBRA1 functions. action: KEEP_AS_NON_CORE reason: This localization is listed in UniProt but was not central to the reviewed autophagy, mitophagy, or CRL4 adaptor evidence. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0006914 label: autophagy evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Autophagy is directionally correct but too broad for the current AMBRA1 evidence. action: MODIFY reason: Direct literature supports AMBRA1 in autophagosome assembly/nucleation and positive regulation of autophagy rather than a generic autophagy process annotation. proposed_replacement_terms: - id: GO:0000045 label: autophagosome assembly - id: GO:0010508 label: positive regulation of autophagy supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20562859 qualifier: enables review: summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited interaction evidence is better represented by specific AMBRA1 activities or complexes, including CRL4 substrate adaptor activity, ubiquitin ligase binding, PP2A binding/activation, and autophagy-scaffold roles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0005515 protein binding` rows as over-annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21358617 qualifier: enables review: summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited interaction evidence is better represented by specific AMBRA1 activities or complexes, including CRL4 substrate adaptor activity, ubiquitin ligase binding, PP2A binding/activation, and autophagy-scaffold roles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0005515 protein binding` rows as over-annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22190034 qualifier: enables review: summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited interaction evidence is better represented by specific AMBRA1 activities or complexes, including CRL4 substrate adaptor activity, ubiquitin ligase binding, PP2A binding/activation, and autophagy-scaffold roles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0005515 protein binding` rows as over-annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23524951 qualifier: enables review: summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited interaction evidence is better represented by specific AMBRA1 activities or complexes, including CRL4 substrate adaptor activity, ubiquitin ligase binding, PP2A binding/activation, and autophagy-scaffold roles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0005515 protein binding` rows as over-annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23954414 qualifier: enables review: summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited interaction evidence is better represented by specific AMBRA1 activities or complexes, including CRL4 substrate adaptor activity, ubiquitin ligase binding, PP2A binding/activation, and autophagy-scaffold roles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0005515 protein binding` rows as over-annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23974797 qualifier: enables review: summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited interaction evidence is better represented by specific AMBRA1 activities or complexes, including CRL4 substrate adaptor activity, ubiquitin ligase binding, PP2A binding/activation, and autophagy-scaffold roles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0005515 protein binding` rows as over-annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25438055 qualifier: enables review: summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited interaction evidence is better represented by specific AMBRA1 activities or complexes, including CRL4 substrate adaptor activity, ubiquitin ligase binding, PP2A binding/activation, and autophagy-scaffold roles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0005515 protein binding` rows as over-annotations. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: Cytoplasmic localization is supported for AMBRA1 autophagy functions. action: ACCEPT reason: AMBRA1 cytoplasmic localization is consistent with its BECN1, dynein, and mitochondrial autophagy interactions. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0005930 label: axoneme evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Axoneme localization is by similarity and should be retained as non-core/contextual. action: KEEP_AS_NON_CORE reason: UniProt reports ciliary axoneme puncta by similarity; no human AMBRA1 core function depends on this localization in the reviewed evidence. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0006357 label: regulation of transcription by RNA polymerase II evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Transcriptional regulation is supported as a nuclear scaffolding role but is not the primary AMBRA1 function. action: KEEP_AS_NON_CORE reason: The human nuclear Ambra1 study supports chromatin-associated transcriptional complexes; this is a context-specific role separate from the core autophagy and CRL4 functions. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 has reported nuclear scaffolding roles in cancer cells - term: id: GO:0009267 label: cellular response to starvation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: cellular response to starvation is a supported context for AMBRA1 autophagy induction but not a core function. action: KEEP_AS_NON_CORE reason: Starvation and nutrient conditions regulate AMBRA1-dependent autophagy, but the core function is autophagosome nucleation/autophagy regulation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0010508 label: positive regulation of autophagy evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: AMBRA1 positively regulates autophagy initiation. action: ACCEPT reason: Multiple studies support AMBRA1 as a positive regulator of BECN1-dependent autophagy and autophagosome initiation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0010667 label: negative regulation of cardiac muscle cell apoptotic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: This apoptosis-related IEA transfer is peripheral and not strongly supported as a human AMBRA1 core process. action: MARK_AS_OVER_ANNOTATED reason: AMBRA1 can connect autophagy and apoptosis through mitochondrial BCL2, but this specific cardiac muscle cell apoptotic-process term appears over-specific for the human evidence reviewed here. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0031667 label: response to nutrient levels evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: response to nutrient levels is a supported context for AMBRA1 autophagy induction but not a core function. action: KEEP_AS_NON_CORE reason: Starvation and nutrient conditions regulate AMBRA1-dependent autophagy, but the core function is autophagosome nucleation/autophagy regulation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0045335 label: phagocytic vesicle evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: The phagocytic vesicle IEA localization is not supported as a useful human AMBRA1 localization. action: MARK_AS_OVER_ANNOTATED reason: Reviewed AMBRA1 evidence emphasizes cytoskeleton, ER, mitochondria, autophagosome/cytosol, nucleus, and focal adhesion/ciliary by-similarity sites rather than phagocytic vesicles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0045591 label: positive regulation of regulatory T cell differentiation evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Regulatory T-cell differentiation is experimentally supported but context-specific. action: KEEP_AS_NON_CORE reason: AMBRA1 acts upstream of FOXO3-FOXP3 through PP2A in Treg differentiation, but this immune-cell outcome is not the primary AMBRA1 molecular function. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 has non-core but supported regulatory roles through PP2A. - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000041 qualifier: involved_in review: summary: Protein ubiquitination is consistent with AMBRA1 CRL4 adaptor and autophagy signaling roles. action: ACCEPT reason: AMBRA1 supports substrate ubiquitination in CRL4 complexes and K63-linked ubiquitination events in autophagy regulation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Multiple 2021 studies identify CRL4AMBRA1 as a cyclin D E3 ligase adaptor controlling G1/S progression through ubiquitin-dependent proteasomal degradation of D-type cyclins - term: id: GO:0031464 label: Cul4A-RING E3 ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:25499913 qualifier: part_of review: summary: Cul4A-RING E3 ubiquitin ligase complex membership is supported by CRL4AMBRA1 literature. action: ACCEPT reason: AMBRA1 dynamically interacts with Cullin-4 complexes and acts as a CRL4 substrate receptor; the Cul4A versus Cul4B distinction is plausible from the CRL4 evidence. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Multiple 2021 studies identify CRL4AMBRA1 as a cyclin D E3 ligase adaptor controlling G1/S progression through ubiquitin-dependent proteasomal degradation of D-type cyclins - term: id: GO:0031465 label: Cul4B-RING E3 ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:25499913 qualifier: part_of review: summary: Cul4B-RING E3 ubiquitin ligase complex membership is supported by CRL4AMBRA1 literature. action: ACCEPT reason: AMBRA1 dynamically interacts with Cullin-4 complexes and acts as a CRL4 substrate receptor; the Cul4A versus Cul4B distinction is plausible from the CRL4 evidence. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Multiple 2021 studies identify CRL4AMBRA1 as a cyclin D E3 ligase adaptor controlling G1/S progression through ubiquitin-dependent proteasomal degradation of D-type cyclins - term: id: GO:1901987 label: regulation of cell cycle phase transition evidence_type: NAS original_reference_id: PMID:25499913 qualifier: involved_in review: summary: Cell-cycle phase-transition regulation is supported but is a downstream outcome of AMBRA1 CRL4 substrate-adaptor activity. action: KEEP_AS_NON_CORE reason: AMBRA1 controls D-type cyclin stability and G1/S entry; the core mechanistic annotation is CRL4 substrate adaptor activity and proteasomal catabolism. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Multiple 2021 studies identify CRL4AMBRA1 as a cyclin D E3 ligase adaptor controlling G1/S progression through ubiquitin-dependent proteasomal degradation of D-type cyclins - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: EXP original_reference_id: PMID:20921139 qualifier: located_in review: summary: Endoplasmic reticulum localization is supported during autophagosome nucleation. action: ACCEPT reason: After autophagy induction, AMBRA1 relocalization to the ER enables autophagosome nucleation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0072542 label: protein phosphatase activator activity evidence_type: IDA original_reference_id: PMID:25438055 qualifier: enables review: summary: AMBRA1 protein phosphatase activator activity is supported for PP2A-dependent targets but is context-specific. action: KEEP_AS_NON_CORE reason: The PP2A/MYC and PP2A/FOXO3 studies support the annotation, but CRL4 adaptor activity and autophagy/mitophagy regulation are the central AMBRA1 functions. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 has non-core but supported regulatory roles through PP2A. - term: id: GO:0072542 label: protein phosphatase activator activity evidence_type: IDA original_reference_id: PMID:30513302 qualifier: enables review: summary: AMBRA1 protein phosphatase activator activity is supported for PP2A-dependent targets but is context-specific. action: KEEP_AS_NON_CORE reason: The PP2A/MYC and PP2A/FOXO3 studies support the annotation, but CRL4 adaptor activity and autophagy/mitophagy regulation are the central AMBRA1 functions. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 has non-core but supported regulatory roles through PP2A. - term: id: GO:0000423 label: mitophagy evidence_type: IGI original_reference_id: PMID:25215947 qualifier: involved_in review: summary: AMBRA1 has direct evidence for roles in mitophagy. action: ACCEPT reason: Parkin-associated, LC3/GABARAP-associated, and HUWE1-associated evidence supports AMBRA1 involvement in mitochondrial clearance. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. - term: id: GO:0051897 label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction evidence_type: IDA original_reference_id: PMID:21753002 qualifier: involved_in review: summary: The Parkin/AMBRA1 evidence supports local class III PI3K activation during mitophagy, not PI3K/AKT signaling. action: MODIFY reason: The biological effect is mitochondrial clearance through Parkin-associated mitophagy; GO:1901526 positive regulation of mitophagy is the conservative replacement. proposed_replacement_terms: - id: GO:1901526 label: positive regulation of mitophagy supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction` as a term-choice problem. - term: id: GO:0000045 label: autophagosome assembly evidence_type: IDA original_reference_id: PMID:23524951 qualifier: involved_in review: summary: AMBRA1 has direct evidence for promoting autophagosome assembly/nucleation. action: ACCEPT reason: AMBRA1 links ULK1 signaling, dynein release, and BECN1-PIK3C3 relocalization during autophagosome nucleation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:33854239 qualifier: involved_in review: summary: Proteasome-mediated ubiquitin-dependent catabolism is a direct output of AMBRA1 CRL4 adaptor activity. action: ACCEPT reason: CRL4AMBRA1 promotes ubiquitin-dependent proteasomal degradation of D-type cyclins, supporting this proteostasis-relevant process. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Multiple 2021 studies identify CRL4AMBRA1 as a cyclin D E3 ligase adaptor controlling G1/S progression through ubiquitin-dependent proteasomal degradation of D-type cyclins - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:33854232 qualifier: involved_in review: summary: Proteasome-mediated ubiquitin-dependent catabolism is a direct output of AMBRA1 CRL4 adaptor activity. action: ACCEPT reason: CRL4AMBRA1 promotes ubiquitin-dependent proteasomal degradation of D-type cyclins, supporting this proteostasis-relevant process. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Multiple 2021 studies identify CRL4AMBRA1 as a cyclin D E3 ligase adaptor controlling G1/S progression through ubiquitin-dependent proteasomal degradation of D-type cyclins - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:33854235 qualifier: involved_in review: summary: Proteasome-mediated ubiquitin-dependent catabolism is a direct output of AMBRA1 CRL4 adaptor activity. action: ACCEPT reason: CRL4AMBRA1 promotes ubiquitin-dependent proteasomal degradation of D-type cyclins, supporting this proteostasis-relevant process. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Multiple 2021 studies identify CRL4AMBRA1 as a cyclin D E3 ligase adaptor controlling G1/S progression through ubiquitin-dependent proteasomal degradation of D-type cyclins - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31123703 qualifier: enables review: summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited interaction evidence is better represented by specific AMBRA1 activities or complexes, including CRL4 substrate adaptor activity, ubiquitin ligase binding, PP2A binding/activation, and autophagy-scaffold roles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0005515 protein binding` rows as over-annotations. - term: id: GO:0000045 label: autophagosome assembly evidence_type: IDA original_reference_id: PMID:20921139 qualifier: involved_in review: summary: AMBRA1 has direct evidence for promoting autophagosome assembly/nucleation. action: ACCEPT reason: AMBRA1 links ULK1 signaling, dynein release, and BECN1-PIK3C3 relocalization during autophagosome nucleation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0000209 label: protein polyubiquitination evidence_type: IDA original_reference_id: PMID:30217973 qualifier: involved_in review: summary: The polyubiquitination annotation is supported, but the cited mitophagy paper is not AMBRA1 direct ligase activity. action: KEEP_AS_NON_CORE reason: In this context AMBRA1 acts with HUWE1 during mitophagy and MFN2 degradation; the direct core function is better captured by mitophagy regulation and CRL4 adaptor activity. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20921139 qualifier: enables review: summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited interaction evidence is better represented by specific AMBRA1 activities or complexes, including CRL4 substrate adaptor activity, ubiquitin ligase binding, PP2A binding/activation, and autophagy-scaffold roles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0005515 protein binding` rows as over-annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:30217973 qualifier: enables review: summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited interaction evidence is better represented by specific AMBRA1 activities or complexes, including CRL4 substrate adaptor activity, ubiquitin ligase binding, PP2A binding/activation, and autophagy-scaffold roles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0005515 protein binding` rows as over-annotations. - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:32616651 qualifier: is_active_in review: summary: Nuclear localization is supported by AMBRA1 nuclear scaffolding studies. action: ACCEPT reason: Human AMBRA1 localizes to the nucleus in cancer cells and scaffolds transcriptional complexes at chromatin. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 has reported nuclear scaffolding roles in cancer cells - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:21358617 qualifier: is_active_in review: summary: Cytoplasmic localization is supported for AMBRA1 autophagy functions. action: ACCEPT reason: AMBRA1 cytoplasmic localization is consistent with its BECN1, dynein, and mitochondrial autophagy interactions. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0005739 label: mitochondrion evidence_type: IDA original_reference_id: PMID:21358617 qualifier: is_active_in review: summary: Mitochondrial localization is supported in AMBRA1 mitophagy/autophagy studies. action: ACCEPT reason: AMBRA1 interacts with mitochondrial BCL2, Parkin-associated depolarized mitochondria, and LC3-dependent mitophagy machinery. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - term: id: GO:0005856 label: cytoskeleton evidence_type: IDA original_reference_id: PMID:20921139 qualifier: is_active_in review: summary: Cytoskeleton localization/activity is supported by AMBRA1 dynein complex tethering. action: ACCEPT reason: The BECN1-VPS34 complex is tethered to the cytoskeleton through AMBRA1 and dynein light chains. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0010508 label: positive regulation of autophagy evidence_type: IDA original_reference_id: PMID:21358617 qualifier: involved_in review: summary: AMBRA1 positively regulates autophagy initiation. action: ACCEPT reason: Multiple studies support AMBRA1 as a positive regulator of BECN1-dependent autophagy and autophagosome initiation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0010508 label: positive regulation of autophagy evidence_type: IDA original_reference_id: PMID:31123703 qualifier: involved_in review: summary: AMBRA1 positively regulates autophagy initiation. action: ACCEPT reason: Multiple studies support AMBRA1 as a positive regulator of BECN1-dependent autophagy and autophagosome initiation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0010508 label: positive regulation of autophagy evidence_type: IMP original_reference_id: PMID:32333458 qualifier: involved_in review: summary: AMBRA1 positively regulates autophagy initiation. action: ACCEPT reason: Multiple studies support AMBRA1 as a positive regulator of BECN1-dependent autophagy and autophagosome initiation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0019903 label: protein phosphatase binding evidence_type: IDA original_reference_id: PMID:25438055 qualifier: enables review: summary: AMBRA1 protein phosphatase binding is supported for PP2A-dependent regulatory contexts but is not a core proteostasis function. action: KEEP_AS_NON_CORE reason: The PP2A/MYC and PP2A/FOXO3 studies support the annotation, but CRL4 adaptor activity and autophagy/mitophagy regulation are the central AMBRA1 functions. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 has non-core but supported regulatory roles through PP2A. - term: id: GO:0019903 label: protein phosphatase binding evidence_type: IDA original_reference_id: PMID:30513302 qualifier: enables review: summary: AMBRA1 protein phosphatase binding is supported for PP2A-dependent regulatory contexts but is not a core proteostasis function. action: KEEP_AS_NON_CORE reason: The PP2A/MYC and PP2A/FOXO3 studies support the annotation, but CRL4 adaptor activity and autophagy/mitophagy regulation are the central AMBRA1 functions. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 has non-core but supported regulatory roles through PP2A. - term: id: GO:0045591 label: positive regulation of regulatory T cell differentiation evidence_type: IDA original_reference_id: PMID:30513302 qualifier: involved_in review: summary: Regulatory T-cell differentiation is experimentally supported but context-specific. action: KEEP_AS_NON_CORE reason: AMBRA1 acts upstream of FOXO3-FOXP3 through PP2A in Treg differentiation, but this immune-cell outcome is not the primary AMBRA1 molecular function. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 has non-core but supported regulatory roles through PP2A. - term: id: GO:0080008 label: Cul4-RING E3 ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:33854235 qualifier: part_of review: summary: AMBRA1 is a CRL4/DDB1-CUL4 substrate receptor/adaptor. action: ACCEPT reason: CRL4AMBRA1 evidence supports AMBRA1 as part of a Cul4-RING E3 ligase complex. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Multiple 2021 studies identify CRL4AMBRA1 as a cyclin D E3 ligase adaptor controlling G1/S progression through ubiquitin-dependent proteasomal degradation of D-type cyclins - term: id: GO:1901526 label: positive regulation of mitophagy evidence_type: IDA original_reference_id: PMID:30217973 qualifier: involved_in review: summary: Positive regulation of mitophagy is directly supported for AMBRA1. action: ACCEPT reason: AMBRA1 promotes mitochondrial clearance through Parkin interaction, LC3 binding, and HUWE1/IKKa-regulated activation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. - term: id: GO:1904544 label: positive regulation of free ubiquitin chain polymerization evidence_type: IDA original_reference_id: PMID:31123703 qualifier: involved_in review: summary: Positive regulation of free ubiquitin chain polymerization is supported in a TRIM32/autophagy context but is not a broad AMBRA1 core function. action: KEEP_AS_NON_CORE reason: The evidence is specific to atrophic muscle-cell autophagy induction through TRIM32 and ULK1, so it should not be generalized as a primary AMBRA1 function. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:23524951 qualifier: enables review: summary: AMBRA1 has core CRL4 substrate-adaptor activity. action: ACCEPT reason: Direct CRL4AMBRA1 studies support AMBRA1 as the substrate-recognition/adaptor component for ELOC and D-type cyclin ubiquitination. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: The PN projection contains an exact existing GOA match for `GO:1990756 ubiquitin-like ligase-substrate adaptor activity` through the UPS CRL4 substrate receptor branch. - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:30166453 qualifier: enables review: summary: AMBRA1 has core CRL4 substrate-adaptor activity. action: ACCEPT reason: Direct CRL4AMBRA1 studies support AMBRA1 as the substrate-recognition/adaptor component for ELOC and D-type cyclin ubiquitination. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: The PN projection contains an exact existing GOA match for `GO:1990756 ubiquitin-like ligase-substrate adaptor activity` through the UPS CRL4 substrate receptor branch. - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:33854232 qualifier: enables review: summary: AMBRA1 has core CRL4 substrate-adaptor activity. action: ACCEPT reason: Direct CRL4AMBRA1 studies support AMBRA1 as the substrate-recognition/adaptor component for ELOC and D-type cyclin ubiquitination. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: The PN projection contains an exact existing GOA match for `GO:1990756 ubiquitin-like ligase-substrate adaptor activity` through the UPS CRL4 substrate receptor branch. - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:33854235 qualifier: enables review: summary: AMBRA1 has core CRL4 substrate-adaptor activity. action: ACCEPT reason: Direct CRL4AMBRA1 studies support AMBRA1 as the substrate-recognition/adaptor component for ELOC and D-type cyclin ubiquitination. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: The PN projection contains an exact existing GOA match for `GO:1990756 ubiquitin-like ligase-substrate adaptor activity` through the UPS CRL4 substrate receptor branch. - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:33854239 qualifier: enables review: summary: AMBRA1 has core CRL4 substrate-adaptor activity. action: ACCEPT reason: Direct CRL4AMBRA1 studies support AMBRA1 as the substrate-recognition/adaptor component for ELOC and D-type cyclin ubiquitination. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: The PN projection contains an exact existing GOA match for `GO:1990756 ubiquitin-like ligase-substrate adaptor activity` through the UPS CRL4 substrate receptor branch. - term: id: GO:2000045 label: regulation of G1/S transition of mitotic cell cycle evidence_type: IDA original_reference_id: PMID:25438055 qualifier: involved_in review: summary: Regulation of G1/S transition is supported but non-core relative to AMBRA1 molecular mechanism. action: KEEP_AS_NON_CORE reason: AMBRA1 affects G1/S progression through PP2A/MYC and CRL4/cyclin D mechanisms; those molecular functions are more specific. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Multiple 2021 studies identify CRL4AMBRA1 as a cyclin D E3 ligase adaptor controlling G1/S progression through ubiquitin-dependent proteasomal degradation of D-type cyclins - term: id: GO:0051020 label: GTPase binding evidence_type: IPI original_reference_id: PMID:25891078 qualifier: enables review: summary: GTPase binding is over-specific for the AMBRA1-IRGM interaction evidence. action: MARK_AS_OVER_ANNOTATED reason: PMID:25891078 supports a physical IRGM-AMBRA1 interaction in autophagy organization, but the broad GTPase-binding term overstates AMBRA1 as a general GTPase-binding effector rather than a context-specific autophagy scaffold partner. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0051020 GTPase binding` from PMID:25891078 as over-annotated for AMBRA1. - term: id: GO:0000045 label: autophagosome assembly evidence_type: IMP original_reference_id: PMID:25215947 qualifier: involved_in review: summary: AMBRA1 has direct evidence for promoting autophagosome assembly/nucleation. action: ACCEPT reason: AMBRA1 links ULK1 signaling, dynein release, and BECN1-PIK3C3 relocalization during autophagosome nucleation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - term: id: GO:0000423 label: mitophagy evidence_type: IDA original_reference_id: PMID:21753002 qualifier: involved_in review: summary: AMBRA1 has direct evidence for roles in mitophagy. action: ACCEPT reason: Parkin-associated, LC3/GABARAP-associated, and HUWE1-associated evidence supports AMBRA1 involvement in mitochondrial clearance. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. - term: id: GO:0000423 label: mitophagy evidence_type: IMP original_reference_id: PMID:25215947 qualifier: involved_in review: summary: AMBRA1 has direct evidence for roles in mitophagy. action: ACCEPT reason: Parkin-associated, LC3/GABARAP-associated, and HUWE1-associated evidence supports AMBRA1 involvement in mitochondrial clearance. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. - term: id: GO:0098780 label: response to mitochondrial depolarisation evidence_type: IDA original_reference_id: PMID:21753002 qualifier: involved_in review: summary: response to mitochondrial depolarisation was reviewed conservatively from cached evidence. action: KEEP_AS_NON_CORE reason: The annotation was not identified as a primary AMBRA1 core function, but no direct contradiction was found in the available cached evidence. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. - term: id: GO:0098780 label: response to mitochondrial depolarisation evidence_type: IGI original_reference_id: PMID:25215947 qualifier: involved_in review: summary: response to mitochondrial depolarisation was reviewed conservatively from cached evidence. action: KEEP_AS_NON_CORE reason: The annotation was not identified as a primary AMBRA1 core function, but no direct contradiction was found in the available cached evidence. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. - term: id: GO:0048471 label: perinuclear region of cytoplasm evidence_type: TAS original_reference_id: PMID:21753002 qualifier: located_in review: summary: Perinuclear cytoplasm localization is supported during depolarized-mitochondria clustering. action: KEEP_AS_NON_CORE reason: The location is mitophagy-context specific and should not be treated as a primary functional annotation. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25127057 qualifier: enables review: summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited interaction evidence is better represented by specific AMBRA1 activities or complexes, including CRL4 substrate adaptor activity, ubiquitin ligase binding, PP2A binding/activation, and autophagy-scaffold roles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0005515 protein binding` rows as over-annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25215947 qualifier: enables review: summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited interaction evidence is better represented by specific AMBRA1 activities or complexes, including CRL4 substrate adaptor activity, ubiquitin ligase binding, PP2A binding/activation, and autophagy-scaffold roles. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Treat `GO:0005515 protein binding` rows as over-annotations. - term: id: GO:0005739 label: mitochondrion evidence_type: IDA original_reference_id: PMID:25215947 qualifier: located_in review: summary: Mitochondrial localization is supported in AMBRA1 mitophagy/autophagy studies. action: ACCEPT reason: AMBRA1 interacts with mitochondrial BCL2, Parkin-associated depolarized mitochondria, and LC3-dependent mitophagy machinery. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - term: id: GO:0005741 label: mitochondrial outer membrane evidence_type: NAS original_reference_id: PMID:25215947 qualifier: located_in review: summary: Mitochondrial outer-membrane association is supported in mitophagy experiments but is context-specific. action: KEEP_AS_NON_CORE reason: AMBRA1 has a mitochondrial pool and forced outer-membrane localization can induce mitophagy; native OMM specificity should be retained conservatively as non-core. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. - term: id: GO:0005739 label: mitochondrion evidence_type: IDA original_reference_id: PMID:21753002 qualifier: colocalizes_with review: summary: Mitochondrial localization is supported in AMBRA1 mitophagy/autophagy studies. action: ACCEPT reason: AMBRA1 interacts with mitochondrial BCL2, Parkin-associated depolarized mitochondria, and LC3-dependent mitophagy machinery. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:21753002 qualifier: located_in review: summary: Cytosol localization is supported by Reactome and AMBRA1 autophagy/mitophagy evidence. action: ACCEPT reason: Cytosolic AMBRA1 complexes with dynein light chains and BECN1 are central to autophagy initiation models. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0031625 label: ubiquitin protein ligase binding evidence_type: IPI original_reference_id: PMID:21753002 qualifier: enables review: summary: Ubiquitin protein ligase binding is supported by AMBRA1 interaction with Parkin in mitophagy. action: ACCEPT reason: Parkin-AMBRA1 interaction is a mechanistic part of AMBRA1-dependent mitochondrial clearance. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. - term: id: GO:0005930 label: axoneme evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Axoneme localization is by similarity and should be retained as non-core/contextual. action: KEEP_AS_NON_CORE reason: UniProt reports ciliary axoneme puncta by similarity; no human AMBRA1 core function depends on this localization in the reviewed evidence. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1632843 qualifier: located_in review: summary: Cytosol localization is supported by Reactome and AMBRA1 autophagy/mitophagy evidence. action: ACCEPT reason: Cytosolic AMBRA1 complexes with dynein light chains and BECN1 are central to autophagy initiation models. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1632857 qualifier: located_in review: summary: Cytosol localization is supported by Reactome and AMBRA1 autophagy/mitophagy evidence. action: ACCEPT reason: Cytosolic AMBRA1 complexes with dynein light chains and BECN1 are central to autophagy initiation models. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5678313 qualifier: located_in review: summary: Cytosol localization is supported by Reactome and AMBRA1 autophagy/mitophagy evidence. action: ACCEPT reason: Cytosolic AMBRA1 complexes with dynein light chains and BECN1 are central to autophagy initiation models. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5678315 qualifier: located_in review: summary: Cytosol localization is supported by Reactome and AMBRA1 autophagy/mitophagy evidence. action: ACCEPT reason: Cytosolic AMBRA1 complexes with dynein light chains and BECN1 are central to autophagy initiation models. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:17589504 qualifier: located_in review: summary: Cytoplasmic localization is supported for AMBRA1 autophagy functions. action: ACCEPT reason: AMBRA1 cytoplasmic localization is consistent with its BECN1, dynein, and mitochondrial autophagy interactions. supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. references: - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000041 title: Gene Ontology annotation based on UniPathway vocabulary mapping findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:17589504 title: Ambra1 regulates autophagy and development of the nervous system. findings: - statement: AMBRA1 was identified as a WD40-domain positive regulator of BECN1-dependent autophagy and neural development. - id: PMID:20562859 title: Network organization of the human autophagy system. findings: - statement: A human autophagy interaction-network study placed AMBRA1/DCAF3 with DDB1-CUL4-DDA1 and the PIK3C3-BECN1 complex. - id: PMID:20921139 title: The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. findings: - statement: AMBRA1 links the dynein-tethered BECN1-VPS34 complex to ULK1-dependent release and ER-associated autophagosome nucleation. - id: PMID:21358617 title: Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy. findings: - statement: AMBRA1 interacts with mitochondrial BCL2 and supports BECN1-dependent autophagy regulation. - id: PMID:21753002 title: Parkin interacts with Ambra1 to induce mitophagy. findings: - statement: AMBRA1 interacts with Parkin and is required for efficient mitochondrial clearance after depolarization. - id: PMID:22190034 title: Global landscape of HIV-human protein complexes. findings: [] - id: PMID:23524951 title: mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. findings: - statement: AMBRA1 and TRAF6 support K63-linked ULK1 ubiquitylation during autophagy induction. - id: PMID:23954414 title: Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. findings: [] - id: PMID:23974797 title: WASH inhibits autophagy through suppression of Beclin 1 ubiquitination. findings: [] - id: PMID:25127057 title: TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition. findings: [] - id: PMID:25215947 title: AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1. findings: - statement: AMBRA1 promotes LC3-dependent mitophagy through a LIR motif in Parkin-dependent and Parkin-independent settings. - id: PMID:25438055 title: AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. findings: - statement: AMBRA1 interacts with PP2A and promotes PP2A-dependent MYC dephosphorylation and degradation. - id: PMID:25499913 title: AMBRA1 interplay with cullin E3 ubiquitin ligases regulates autophagy dynamics. findings: - statement: Cullin-4 and Cullin-5 dynamically interact with AMBRA1 to regulate onset and termination of autophagy. - id: PMID:25891078 title: IRGM governs the core autophagy machinery to conduct antimicrobial defense. findings: - statement: The cached IRGM paper supports IRGM organization of autophagy regulators but does not establish AMBRA1 GTPase-binding activity. - id: PMID:30166453 title: CRL4(AMBRA1) targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling. findings: - statement: CRL4AMBRA1 targets ELOC for ubiquitination and degradation, modulating CRL5 signaling. - id: PMID:30217973 title: "HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKK\u03B1." findings: - statement: HUWE1 and IKKa regulate AMBRA1-mediated mitophagy and MFN2 degradation. - id: PMID:30513302 title: AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis. findings: - statement: AMBRA1 supports regulatory T-cell differentiation through PP2A- and FOXO3-associated mechanisms. - id: PMID:31123703 title: Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains. findings: - statement: TRIM32 binds AMBRA1 and ULK1 and stimulates ULK1 activity through unanchored K63-linked polyubiquitin in atrophic muscle cells. - id: PMID:32333458 title: Rare mutations in the autophagy-regulating gene AMBRA1 contribute to human neural tube defects. findings: - statement: Human AMBRA1 variants impair autophagy initiation and may contribute to neural tube defects. - id: PMID:32616651 title: The autophagy protein Ambra1 regulates gene expression by supporting novel transcriptional complexes. findings: - statement: AMBRA1 has nuclear scaffolding roles at chromatin-associated transcriptional complexes. - id: PMID:33854232 title: AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity. findings: - statement: AMBRA1 regulates cyclin D abundance to guard S-phase entry and genomic integrity. - id: PMID:33854235 title: CRL4(AMBRA1) is a master regulator of D-type cyclins. findings: - statement: CRL4AMBRA1 targets all three D-type cyclins for degradation. - id: PMID:33854239 title: "The AMBRA1 E3 ligase adaptor regulates the stability of cyclin\_D." findings: - statement: AMBRA1 mediates ubiquitylation and proteasomal degradation of cyclin D as a CRL4 substrate receptor. - id: PMID:34362797 title: "AMBRA1 Promotes TGFβ Signaling via Nonproteolytic Polyubiquitylation of Smad4." full_text_unavailable: true findings: - statement: AMBRA1 acts as the CRL4 (CRL4-AMBRA1/DCAF3) substrate receptor for Smad4 and mediates nonproteolytic polyubiquitylation of Smad4 that enhances its transcriptional functions and potentiates TGFbeta signaling. - id: PMID:37993427 title: Structure of the DDB1-AMBRA1 E3 ligase receptor complex linked to cell cycle regulation. full_text_unavailable: true findings: - statement: A 3.08 Angstrom cryo-EM structure shows AMBRA1 N- and C-terminal regions fold together into a split WD40 domain that binds DDB1, and DDB1 binding-defective AMBRA1 mutants prevent Cyclin D1 ubiquitination and increase cell cycle progression. - id: Reactome:R-HSA-1632843 title: AMBRA1 binds DYNLL1,DYNLL2 findings: - statement: Reactome represents cytosolic AMBRA1 binding to dynein light chains DYNLL1 and DYNLL2. - id: Reactome:R-HSA-1632857 title: ULK1 phosphorylates AMBRA1:BECN1 complex findings: - statement: Reactome represents ULK1 phosphorylation of the AMBRA1:BECN1 complex. - id: Reactome:R-HSA-5678313 title: AMBRA1:DYNLL1,DYNLL2 binds BECN1 complex findings: - statement: Reactome represents AMBRA1:DYNLL1,DYNLL2 binding to the BECN1 complex. - id: Reactome:R-HSA-5678315 title: BECN1 complex, p-AMBRA1 dissociate from DYNLL1,DYNLL2 findings: - statement: Reactome represents dissociation of the BECN1 complex and phosphorylated AMBRA1 from dynein light chains. - id: file:human/AMBRA1/AMBRA1-uniprot.txt title: UniProtKB record for human AMBRA1 findings: - statement: UniProt summarizes AMBRA1 as a DCX/DDB1-CUL4 substrate-recognition component involved in autophagy and cell-cycle control. - statement: UniProt lists cytoskeleton, ER, mitochondrion, nucleus, focal adhesion, and by-similarity ciliary axoneme localizations. - id: file:human/AMBRA1/AMBRA1-notes.md title: Manual AMBRA1 PN review notes findings: - statement: Notes record the failed Falcon/fallback deep-research attempt, literature synthesis, and conservative PN projection assessment. - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv title: Proteostasis PN projected annotations report findings: - statement: The PN projection lists AMBRA1 as already matching GO:1990756 and as a candidate for GO:1904716 from a CMA enhancer branch. - id: file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml title: Proteostasis autophagy-lysosome pathway mapping findings: - statement: The AMBRA1-specific CMA enhancer leaf is marked no_mapping as contextual and not sufficient for universal GO assertion. - id: file:projects/PROTEOSTASIS/mappings/ubiquitin_proteasome_system.yaml title: Proteostasis ubiquitin-proteasome system mapping findings: - statement: The Cul4A/Cul4B substrate receptor group maps to GO:1990756 and covers CRL4 substrate receptors/adaptors. core_functions: - molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity description: AMBRA1 acts as the substrate-recognition/adaptor component of CRL4/DDB1-CUL4 E3 ubiquitin ligase complexes, promoting ubiquitination and proteasome-mediated degradation of substrates including ELOC and D-type cyclins. directly_involved_in: - id: GO:0016567 label: protein ubiquitination - id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process locations: - id: GO:0005829 label: cytosol - id: GO:0005634 label: nucleus in_complex: id: GO:0080008 label: Cul4-RING E3 ubiquitin ligase complex supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: Multiple 2021 studies identify CRL4AMBRA1 as a cyclin D E3 ligase adaptor controlling G1/S progression through ubiquitin-dependent proteasomal degradation of D-type cyclins - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: The PN projection contains an exact existing GOA match for `GO:1990756 ubiquitin-like ligase-substrate adaptor activity` through the UPS CRL4 substrate receptor branch. - description: AMBRA1 is an autophagy-initiation scaffold that couples ULK1 signaling to BECN1-PIK3C3 complex release and ER-associated autophagosome nucleation. directly_involved_in: - id: GO:0000045 label: autophagosome assembly - id: GO:0010508 label: positive regulation of autophagy locations: - id: GO:0005856 label: cytoskeleton - id: GO:0005783 label: endoplasmic reticulum - id: GO:0005776 label: autophagosome supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. - molecular_function: id: GO:0031625 label: ubiquitin protein ligase binding description: AMBRA1 promotes mitophagy by engaging Parkin/PRKN, LC3/GABARAP proteins, and HUWE1-associated regulation to drive mitochondrial clearance. directly_involved_in: - id: GO:0000423 label: mitophagy - id: GO:1901526 label: positive regulation of mitophagy locations: - id: GO:0005739 label: mitochondrion - id: GO:0005776 label: autophagosome supported_by: - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 is a mitophagy regulator. - reference_id: file:human/AMBRA1/AMBRA1-notes.md supporting_text: AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. proposed_new_terms: [] suggested_questions: - question: Should AMBRA1 be excluded from automated propagation to GO:1904716 positive regulation of chaperone-mediated autophagy until direct LAMP2A/HSPA8-dependent CMA substrate-uptake evidence is available? experts: - GO autophagy editors - Proteostasis PN curators - question: Should AMBRA1 autophagy-scaffold activity have a more specific molecular-function representation than generic protein binding while avoiding overstatement of direct catalytic activity? experts: - GO molecular-function editors - Autophagy domain experts - question: Does AMBRA1 CRL4 substrate-adaptor activity warrant separate process annotations for nonproteolytic (activity-enhancing) substrate polyubiquitylation, given the CRL4-AMBRA1-mediated nonproteolytic polyubiquitylation of Smad4 that potentiates TGFbeta signaling, distinct from the degradative cyclin-D/ELOC branch? experts: - GO molecular-function editors - Ubiquitin-proteasome system curators suggested_experiments: - description: Test AMBRA1 knockdown and rescue with wild-type, CRL4-binding-deficient, and LC3-LIR-mutant constructs in LAMP2A/HSPA8-dependent CMA substrate-uptake reporter assays. hypothesis: Direct CMA evidence would be required before assigning AMBRA1 to positive regulation of chaperone-mediated autophagy. experiment_type: CMA reporter and rescue assay - description: Compare AMBRA1 wild-type, LIR-mutant, DDB1-binding-deficient, and PP2A-interaction-deficient rescue in autophagosome nucleation, mitophagy, cyclin D/ELOC degradation, and MYC/FOXO3 stability assays. hypothesis: AMBRA1 separable interaction surfaces underlie distinct autophagy-initiation, mitophagy, CRL4-adaptor, and PP2A regulatory functions. experiment_type: structure-function rescue assay - description: Use the DDB1-binding-deficient AMBRA1 interface mutants (e.g., V10/L13) defined by the cryo-EM structure to test whether DDB1 engagement is required for both degradative substrate ubiquitylation (cyclin D1) and nonproteolytic Smad4 polyubiquitylation in parallel ubiquitylation and TGFbeta reporter assays. hypothesis: A single DDB1-binding interface on AMBRA1 underlies both proteolytic and nonproteolytic CRL4-AMBRA1 substrate-ubiquitylation outcomes, with substrate identity rather than the adaptor interface determining the ubiquitin-chain fate. experiment_type: structure-guided ubiquitylation and reporter assay