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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000045 autophagosome assembly | IBA GO_REF:0000033 | ACCEPT | Summary: AMBRA1 has direct evidence for promoting autophagosome assembly/nucleation. Reason: AMBRA1 links ULK1 signaling, dynein release, and BECN1-PIK3C3 relocalization during autophagosome nucleation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0000423 mitophagy | IBA GO_REF:0000033 | ACCEPT | Summary: AMBRA1 has direct evidence for roles in mitophagy. Reason: Parkin-associated, LC3/GABARAP-associated, and HUWE1-associated evidence supports AMBRA1 involvement in mitochondrial clearance. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. |
| GO:0080008 Cul4-RING E3 ubiquitin ligase complex | IBA GO_REF:0000033 | ACCEPT | Summary: AMBRA1 is a CRL4/DDB1-CUL4 substrate receptor/adaptor. Reason: CRL4AMBRA1 evidence supports AMBRA1 as part of a Cul4-RING E3 ligase complex. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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 |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: AMBRA1 has core CRL4 substrate-adaptor activity. Reason: Direct CRL4AMBRA1 studies support AMBRA1 as the substrate-recognition/adaptor component for ELOC and D-type cyclin ubiquitination. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization is supported by AMBRA1 nuclear scaffolding studies. Reason: Human AMBRA1 localizes to the nucleus in cancer cells and scaffolds transcriptional complexes at chromatin. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 has reported nuclear scaffolding roles in cancer cells |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: Mitochondrial localization is supported in AMBRA1 mitophagy/autophagy studies. Reason: AMBRA1 interacts with mitochondrial BCL2, Parkin-associated depolarized mitochondria, and LC3-dependent mitophagy machinery. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. |
| GO:0005776 autophagosome | IEA GO_REF:0000044 | ACCEPT | Summary: Autophagosome localization is consistent with AMBRA1 autophagy and mitophagy roles. Reason: AMBRA1 binds LC3 during mitophagy and acts at autophagosome nucleation steps. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | ACCEPT | Summary: Endoplasmic reticulum localization is supported during autophagosome nucleation. Reason: After autophagy induction, AMBRA1 relocalization to the ER enables autophagosome nucleation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Cytosol localization is supported by Reactome and AMBRA1 autophagy/mitophagy evidence. Reason: Cytosolic AMBRA1 complexes with dynein light chains and BECN1 are central to autophagy initiation models. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0005856 cytoskeleton | IEA GO_REF:0000120 | ACCEPT | Summary: Cytoskeleton localization/activity is supported by AMBRA1 dynein complex tethering. Reason: The BECN1-VPS34 complex is tethered to the cytoskeleton through AMBRA1 and dynein light chains. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0005925 focal adhesion | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Focal adhesion localization is plausible but peripheral to the core AMBRA1 functions. Reason: This localization is listed in UniProt but was not central to the reviewed autophagy, mitophagy, or CRL4 adaptor evidence. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0006914 autophagy | IEA GO_REF:0000117 | MODIFY | Summary: Autophagy is directionally correct but too broad for the current AMBRA1 evidence. Reason: Direct literature supports AMBRA1 in autophagosome assembly/nucleation and positive regulation of autophagy rather than a generic autophagy process annotation. Proposed replacements: autophagosome assembly positive regulation of autophagy Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | MARK AS OVER ANNOTATED | Summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0005515 protein binding` rows as over-annotations. |
| GO:0005515 protein binding | IPI PMID:21358617 Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy. | MARK AS OVER ANNOTATED | Summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0005515 protein binding` rows as over-annotations. |
| GO:0005515 protein binding | IPI PMID:22190034 Global landscape of HIV-human protein complexes. | MARK AS OVER ANNOTATED | Summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0005515 protein binding` rows as over-annotations. |
| GO:0005515 protein binding | IPI PMID:23524951 mTOR inhibits autophagy by controlling ULK1 ubiquitylation, ... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0005515 protein binding` rows as over-annotations. |
| GO:0005515 protein binding | IPI PMID:23954414 Beclin 2 functions in autophagy, degradation of G protein-co... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0005515 protein binding` rows as over-annotations. |
| GO:0005515 protein binding | IPI PMID:23974797 WASH inhibits autophagy through suppression of Beclin 1 ubiq... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0005515 protein binding` rows as over-annotations. |
| GO:0005515 protein binding | IPI PMID:25438055 AMBRA1 links autophagy to cell proliferation and tumorigenes... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0005515 protein binding` rows as over-annotations. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | ACCEPT | Summary: Cytoplasmic localization is supported for AMBRA1 autophagy functions. Reason: AMBRA1 cytoplasmic localization is consistent with its BECN1, dynein, and mitochondrial autophagy interactions. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0005930 axoneme | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Axoneme localization is by similarity and should be retained as non-core/contextual. Reason: UniProt reports ciliary axoneme puncta by similarity; no human AMBRA1 core function depends on this localization in the reviewed evidence. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0006357 regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transcriptional regulation is supported as a nuclear scaffolding role but is not the primary AMBRA1 function. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 has reported nuclear scaffolding roles in cancer cells |
| GO:0009267 cellular response to starvation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: cellular response to starvation is a supported context for AMBRA1 autophagy induction but not a core function. Reason: Starvation and nutrient conditions regulate AMBRA1-dependent autophagy, but the core function is autophagosome nucleation/autophagy regulation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0010508 positive regulation of autophagy | IEA GO_REF:0000120 | ACCEPT | Summary: AMBRA1 positively regulates autophagy initiation. Reason: Multiple studies support AMBRA1 as a positive regulator of BECN1-dependent autophagy and autophagosome initiation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This apoptosis-related IEA transfer is peripheral and not strongly supported as a human AMBRA1 core process. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0031667 response to nutrient levels | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to nutrient levels is a supported context for AMBRA1 autophagy induction but not a core function. Reason: Starvation and nutrient conditions regulate AMBRA1-dependent autophagy, but the core function is autophagosome nucleation/autophagy regulation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0045335 phagocytic vesicle | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The phagocytic vesicle IEA localization is not supported as a useful human AMBRA1 localization. Reason: Reviewed AMBRA1 evidence emphasizes cytoskeleton, ER, mitochondria, autophagosome/cytosol, nucleus, and focal adhesion/ciliary by-similarity sites rather than phagocytic vesicles. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0045591 positive regulation of regulatory T cell differentiation | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Regulatory T-cell differentiation is experimentally supported but context-specific. Reason: AMBRA1 acts upstream of FOXO3-FOXP3 through PP2A in Treg differentiation, but this immune-cell outcome is not the primary AMBRA1 molecular function. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 has non-core but supported regulatory roles through PP2A. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | ACCEPT | Summary: Protein ubiquitination is consistent with AMBRA1 CRL4 adaptor and autophagy signaling roles. Reason: AMBRA1 supports substrate ubiquitination in CRL4 complexes and K63-linked ubiquitination events in autophagy regulation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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 |
| GO:0031464 Cul4A-RING E3 ubiquitin ligase complex | NAS PMID:25499913 AMBRA1 interplay with cullin E3 ubiquitin ligases regulates ... | ACCEPT | Summary: Cul4A-RING E3 ubiquitin ligase complex membership is supported by CRL4AMBRA1 literature. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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 |
| GO:0031465 Cul4B-RING E3 ubiquitin ligase complex | NAS PMID:25499913 AMBRA1 interplay with cullin E3 ubiquitin ligases regulates ... | ACCEPT | Summary: Cul4B-RING E3 ubiquitin ligase complex membership is supported by CRL4AMBRA1 literature. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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 |
| GO:1901987 regulation of cell cycle phase transition | NAS PMID:25499913 AMBRA1 interplay with cullin E3 ubiquitin ligases regulates ... | KEEP AS NON CORE | Summary: Cell-cycle phase-transition regulation is supported but is a downstream outcome of AMBRA1 CRL4 substrate-adaptor activity. Reason: AMBRA1 controls D-type cyclin stability and G1/S entry; the core mechanistic annotation is CRL4 substrate adaptor activity and proteasomal catabolism. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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 |
| GO:0005783 endoplasmic reticulum | EXP PMID:20921139 The dynamic interaction of AMBRA1 with the dynein motor comp... | ACCEPT | Summary: Endoplasmic reticulum localization is supported during autophagosome nucleation. Reason: After autophagy induction, AMBRA1 relocalization to the ER enables autophagosome nucleation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0072542 protein phosphatase activator activity | IDA PMID:25438055 AMBRA1 links autophagy to cell proliferation and tumorigenes... | KEEP AS NON CORE | Summary: AMBRA1 protein phosphatase activator activity is supported for PP2A-dependent targets but is context-specific. Reason: The PP2A/MYC and PP2A/FOXO3 studies support the annotation, but CRL4 adaptor activity and autophagy/mitophagy regulation are the central AMBRA1 functions. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 has non-core but supported regulatory roles through PP2A. |
| GO:0072542 protein phosphatase activator activity | IDA PMID:30513302 AMBRA1 Controls Regulatory T-Cell Differentiation and Homeos... | KEEP AS NON CORE | Summary: AMBRA1 protein phosphatase activator activity is supported for PP2A-dependent targets but is context-specific. Reason: The PP2A/MYC and PP2A/FOXO3 studies support the annotation, but CRL4 adaptor activity and autophagy/mitophagy regulation are the central AMBRA1 functions. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 has non-core but supported regulatory roles through PP2A. |
| GO:0000423 mitophagy | IGI PMID:25215947 AMBRA1 is able to induce mitophagy via LC3 binding, regardle... | ACCEPT | Summary: AMBRA1 has direct evidence for roles in mitophagy. Reason: Parkin-associated, LC3/GABARAP-associated, and HUWE1-associated evidence supports AMBRA1 involvement in mitochondrial clearance. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IDA PMID:21753002 Parkin interacts with Ambra1 to induce mitophagy. | MODIFY | Summary: The Parkin/AMBRA1 evidence supports local class III PI3K activation during mitophagy, not PI3K/AKT signaling. Reason: The biological effect is mitochondrial clearance through Parkin-associated mitophagy; GO:1901526 positive regulation of mitophagy is the conservative replacement. Proposed replacements: positive regulation of mitophagy Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction` as a term-choice problem. |
| GO:0000045 autophagosome assembly | IDA PMID:23524951 mTOR inhibits autophagy by controlling ULK1 ubiquitylation, ... | ACCEPT | Summary: AMBRA1 has direct evidence for promoting autophagosome assembly/nucleation. Reason: AMBRA1 links ULK1 signaling, dynein release, and BECN1-PIK3C3 relocalization during autophagosome nucleation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:33854239 The AMBRA1 E3 ligase adaptor regulates the stability of cycl... | ACCEPT | Summary: Proteasome-mediated ubiquitin-dependent catabolism is a direct output of AMBRA1 CRL4 adaptor activity. Reason: CRL4AMBRA1 promotes ubiquitin-dependent proteasomal degradation of D-type cyclins, supporting this proteostasis-relevant process. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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 |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:33854232 AMBRA1 regulates cyclin D to guard S-phase entry and genomic... | ACCEPT | Summary: Proteasome-mediated ubiquitin-dependent catabolism is a direct output of AMBRA1 CRL4 adaptor activity. Reason: CRL4AMBRA1 promotes ubiquitin-dependent proteasomal degradation of D-type cyclins, supporting this proteostasis-relevant process. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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 |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:33854235 CRL4(AMBRA1) is a master regulator of D-type cyclins. | ACCEPT | Summary: Proteasome-mediated ubiquitin-dependent catabolism is a direct output of AMBRA1 CRL4 adaptor activity. Reason: CRL4AMBRA1 promotes ubiquitin-dependent proteasomal degradation of D-type cyclins, supporting this proteostasis-relevant process. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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 |
| GO:0005515 protein binding | IPI PMID:31123703 Autophagy induction in atrophic muscle cells requires ULK1 a... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0005515 protein binding` rows as over-annotations. |
| GO:0000045 autophagosome assembly | IDA PMID:20921139 The dynamic interaction of AMBRA1 with the dynein motor comp... | ACCEPT | Summary: AMBRA1 has direct evidence for promoting autophagosome assembly/nucleation. Reason: AMBRA1 links ULK1 signaling, dynein release, and BECN1-PIK3C3 relocalization during autophagosome nucleation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0000209 protein polyubiquitination | IDA PMID:30217973 HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy ... | KEEP AS NON CORE | Summary: The polyubiquitination annotation is supported, but the cited mitophagy paper is not AMBRA1 direct ligase activity. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. |
| GO:0005515 protein binding | IPI PMID:20921139 The dynamic interaction of AMBRA1 with the dynein motor comp... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0005515 protein binding` rows as over-annotations. |
| GO:0005515 protein binding | IPI PMID:30217973 HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy ... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0005515 protein binding` rows as over-annotations. |
| GO:0005634 nucleus | IDA PMID:32616651 The autophagy protein Ambra1 regulates gene expression by su... | ACCEPT | Summary: Nuclear localization is supported by AMBRA1 nuclear scaffolding studies. Reason: Human AMBRA1 localizes to the nucleus in cancer cells and scaffolds transcriptional complexes at chromatin. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 has reported nuclear scaffolding roles in cancer cells |
| GO:0005737 cytoplasm | IDA PMID:21358617 Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy. | ACCEPT | Summary: Cytoplasmic localization is supported for AMBRA1 autophagy functions. Reason: AMBRA1 cytoplasmic localization is consistent with its BECN1, dynein, and mitochondrial autophagy interactions. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0005739 mitochondrion | IDA PMID:21358617 Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy. | ACCEPT | Summary: Mitochondrial localization is supported in AMBRA1 mitophagy/autophagy studies. Reason: AMBRA1 interacts with mitochondrial BCL2, Parkin-associated depolarized mitochondria, and LC3-dependent mitophagy machinery. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. |
| GO:0005856 cytoskeleton | IDA PMID:20921139 The dynamic interaction of AMBRA1 with the dynein motor comp... | ACCEPT | Summary: Cytoskeleton localization/activity is supported by AMBRA1 dynein complex tethering. Reason: The BECN1-VPS34 complex is tethered to the cytoskeleton through AMBRA1 and dynein light chains. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0010508 positive regulation of autophagy | IDA PMID:21358617 Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy. | ACCEPT | Summary: AMBRA1 positively regulates autophagy initiation. Reason: Multiple studies support AMBRA1 as a positive regulator of BECN1-dependent autophagy and autophagosome initiation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0010508 positive regulation of autophagy | IDA PMID:31123703 Autophagy induction in atrophic muscle cells requires ULK1 a... | ACCEPT | Summary: AMBRA1 positively regulates autophagy initiation. Reason: Multiple studies support AMBRA1 as a positive regulator of BECN1-dependent autophagy and autophagosome initiation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0010508 positive regulation of autophagy | IMP PMID:32333458 Rare mutations in the autophagy-regulating gene AMBRA1 contr... | ACCEPT | Summary: AMBRA1 positively regulates autophagy initiation. Reason: Multiple studies support AMBRA1 as a positive regulator of BECN1-dependent autophagy and autophagosome initiation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0019903 protein phosphatase binding | IDA PMID:25438055 AMBRA1 links autophagy to cell proliferation and tumorigenes... | KEEP AS NON CORE | Summary: AMBRA1 protein phosphatase binding is supported for PP2A-dependent regulatory contexts but is not a core proteostasis function. Reason: The PP2A/MYC and PP2A/FOXO3 studies support the annotation, but CRL4 adaptor activity and autophagy/mitophagy regulation are the central AMBRA1 functions. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 has non-core but supported regulatory roles through PP2A. |
| GO:0019903 protein phosphatase binding | IDA PMID:30513302 AMBRA1 Controls Regulatory T-Cell Differentiation and Homeos... | KEEP AS NON CORE | Summary: AMBRA1 protein phosphatase binding is supported for PP2A-dependent regulatory contexts but is not a core proteostasis function. Reason: The PP2A/MYC and PP2A/FOXO3 studies support the annotation, but CRL4 adaptor activity and autophagy/mitophagy regulation are the central AMBRA1 functions. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 has non-core but supported regulatory roles through PP2A. |
| GO:0045591 positive regulation of regulatory T cell differentiation | IDA PMID:30513302 AMBRA1 Controls Regulatory T-Cell Differentiation and Homeos... | KEEP AS NON CORE | Summary: Regulatory T-cell differentiation is experimentally supported but context-specific. Reason: AMBRA1 acts upstream of FOXO3-FOXP3 through PP2A in Treg differentiation, but this immune-cell outcome is not the primary AMBRA1 molecular function. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 has non-core but supported regulatory roles through PP2A. |
| GO:0080008 Cul4-RING E3 ubiquitin ligase complex | IDA PMID:33854235 CRL4(AMBRA1) is a master regulator of D-type cyclins. | ACCEPT | Summary: AMBRA1 is a CRL4/DDB1-CUL4 substrate receptor/adaptor. Reason: CRL4AMBRA1 evidence supports AMBRA1 as part of a Cul4-RING E3 ligase complex. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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 |
| GO:1901526 positive regulation of mitophagy | IDA PMID:30217973 HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy ... | ACCEPT | Summary: Positive regulation of mitophagy is directly supported for AMBRA1. Reason: AMBRA1 promotes mitochondrial clearance through Parkin interaction, LC3 binding, and HUWE1/IKKa-regulated activation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. |
| GO:1904544 positive regulation of free ubiquitin chain polymerization | IDA PMID:31123703 Autophagy induction in atrophic muscle cells requires ULK1 a... | KEEP AS NON CORE | Summary: Positive regulation of free ubiquitin chain polymerization is supported in a TRIM32/autophagy context but is not a broad AMBRA1 core function. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:23524951 mTOR inhibits autophagy by controlling ULK1 ubiquitylation, ... | ACCEPT | Summary: AMBRA1 has core CRL4 substrate-adaptor activity. Reason: Direct CRL4AMBRA1 studies support AMBRA1 as the substrate-recognition/adaptor component for ELOC and D-type cyclin ubiquitination. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:30166453 CRL4(AMBRA1) targets Elongin C for ubiquitination and degrad... | ACCEPT | Summary: AMBRA1 has core CRL4 substrate-adaptor activity. Reason: Direct CRL4AMBRA1 studies support AMBRA1 as the substrate-recognition/adaptor component for ELOC and D-type cyclin ubiquitination. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:33854232 AMBRA1 regulates cyclin D to guard S-phase entry and genomic... | ACCEPT | Summary: AMBRA1 has core CRL4 substrate-adaptor activity. Reason: Direct CRL4AMBRA1 studies support AMBRA1 as the substrate-recognition/adaptor component for ELOC and D-type cyclin ubiquitination. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:33854235 CRL4(AMBRA1) is a master regulator of D-type cyclins. | ACCEPT | Summary: AMBRA1 has core CRL4 substrate-adaptor activity. Reason: Direct CRL4AMBRA1 studies support AMBRA1 as the substrate-recognition/adaptor component for ELOC and D-type cyclin ubiquitination. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:33854239 The AMBRA1 E3 ligase adaptor regulates the stability of cycl... | ACCEPT | Summary: AMBRA1 has core CRL4 substrate-adaptor activity. Reason: Direct CRL4AMBRA1 studies support AMBRA1 as the substrate-recognition/adaptor component for ELOC and D-type cyclin ubiquitination. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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. |
| GO:2000045 regulation of G1/S transition of mitotic cell cycle | IDA PMID:25438055 AMBRA1 links autophagy to cell proliferation and tumorigenes... | KEEP AS NON CORE | Summary: Regulation of G1/S transition is supported but non-core relative to AMBRA1 molecular mechanism. Reason: AMBRA1 affects G1/S progression through PP2A/MYC and CRL4/cyclin D mechanisms; those molecular functions are more specific. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 functions as a CRL4/DDB1-CUL4 substrate receptor. file:human/AMBRA1/AMBRA1-notes.md 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 |
| GO:0051020 GTPase binding | IPI PMID:25891078 IRGM governs the core autophagy machinery to conduct antimic... | MARK AS OVER ANNOTATED | Summary: GTPase binding is over-specific for the AMBRA1-IRGM interaction evidence. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0051020 GTPase binding` from PMID:25891078 as over-annotated for AMBRA1. |
| GO:0000045 autophagosome assembly | IMP PMID:25215947 AMBRA1 is able to induce mitophagy via LC3 binding, regardle... | ACCEPT | Summary: AMBRA1 has direct evidence for promoting autophagosome assembly/nucleation. Reason: AMBRA1 links ULK1 signaling, dynein release, and BECN1-PIK3C3 relocalization during autophagosome nucleation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 links ULK1 activation to the BECN1-PIK3C3 complex. |
| GO:0000423 mitophagy | IDA PMID:21753002 Parkin interacts with Ambra1 to induce mitophagy. | ACCEPT | Summary: AMBRA1 has direct evidence for roles in mitophagy. Reason: Parkin-associated, LC3/GABARAP-associated, and HUWE1-associated evidence supports AMBRA1 involvement in mitochondrial clearance. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. |
| GO:0000423 mitophagy | IMP PMID:25215947 AMBRA1 is able to induce mitophagy via LC3 binding, regardle... | ACCEPT | Summary: AMBRA1 has direct evidence for roles in mitophagy. Reason: Parkin-associated, LC3/GABARAP-associated, and HUWE1-associated evidence supports AMBRA1 involvement in mitochondrial clearance. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. |
| GO:0098780 response to mitochondrial depolarisation | IDA PMID:21753002 Parkin interacts with Ambra1 to induce mitophagy. | KEEP AS NON CORE | Summary: response to mitochondrial depolarisation was reviewed conservatively from cached evidence. Reason: The annotation was not identified as a primary AMBRA1 core function, but no direct contradiction was found in the available cached evidence. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. |
| GO:0098780 response to mitochondrial depolarisation | IGI PMID:25215947 AMBRA1 is able to induce mitophagy via LC3 binding, regardle... | KEEP AS NON CORE | Summary: response to mitochondrial depolarisation was reviewed conservatively from cached evidence. Reason: The annotation was not identified as a primary AMBRA1 core function, but no direct contradiction was found in the available cached evidence. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. |
| GO:0048471 perinuclear region of cytoplasm | TAS PMID:21753002 Parkin interacts with Ambra1 to induce mitophagy. | KEEP AS NON CORE | Summary: Perinuclear cytoplasm localization is supported during depolarized-mitochondria clustering. Reason: The location is mitophagy-context specific and should not be treated as a primary functional annotation. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. |
| GO:0005515 protein binding | IPI PMID:25127057 TRIM proteins regulate autophagy and can target autophagic s... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0005515 protein binding` rows as over-annotations. |
| GO:0005515 protein binding | IPI PMID:25215947 AMBRA1 is able to induce mitophagy via LC3 binding, regardle... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is not an informative AMBRA1 molecular-function annotation. 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. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md Treat `GO:0005515 protein binding` rows as over-annotations. |
| GO:0005739 mitochondrion | IDA PMID:25215947 AMBRA1 is able to induce mitophagy via LC3 binding, regardle... | ACCEPT | Summary: Mitochondrial localization is supported in AMBRA1 mitophagy/autophagy studies. Reason: AMBRA1 interacts with mitochondrial BCL2, Parkin-associated depolarized mitochondria, and LC3-dependent mitophagy machinery. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. |
| GO:0005741 mitochondrial outer membrane | NAS PMID:25215947 AMBRA1 is able to induce mitophagy via LC3 binding, regardle... | KEEP AS NON CORE | Summary: Mitochondrial outer-membrane association is supported in mitophagy experiments but is context-specific. Reason: AMBRA1 has a mitochondrial pool and forced outer-membrane localization can induce mitophagy; native OMM specificity should be retained conservatively as non-core. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. |
| GO:0005739 mitochondrion | IDA PMID:21753002 Parkin interacts with Ambra1 to induce mitophagy. | ACCEPT | Summary: Mitochondrial localization is supported in AMBRA1 mitophagy/autophagy studies. Reason: AMBRA1 interacts with mitochondrial BCL2, Parkin-associated depolarized mitochondria, and LC3-dependent mitophagy machinery. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. |
| GO:0005829 cytosol | IDA PMID:21753002 Parkin interacts with Ambra1 to induce mitophagy. | ACCEPT | Summary: Cytosol localization is supported by Reactome and AMBRA1 autophagy/mitophagy evidence. Reason: Cytosolic AMBRA1 complexes with dynein light chains and BECN1 are central to autophagy initiation models. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:21753002 Parkin interacts with Ambra1 to induce mitophagy. | ACCEPT | Summary: Ubiquitin protein ligase binding is supported by AMBRA1 interaction with Parkin in mitophagy. Reason: Parkin-AMBRA1 interaction is a mechanistic part of AMBRA1-dependent mitochondrial clearance. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a mitophagy regulator. file:human/AMBRA1/AMBRA1-notes.md AMBRA1 can promote LC3-dependent mitophagy through its LIR motif in both PARKIN-dependent and PARKIN-independent contexts. |
| GO:0005930 axoneme | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Axoneme localization is by similarity and should be retained as non-core/contextual. Reason: UniProt reports ciliary axoneme puncta by similarity; no human AMBRA1 core function depends on this localization in the reviewed evidence. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1632843 | ACCEPT | Summary: Cytosol localization is supported by Reactome and AMBRA1 autophagy/mitophagy evidence. Reason: Cytosolic AMBRA1 complexes with dynein light chains and BECN1 are central to autophagy initiation models. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1632857 | ACCEPT | Summary: Cytosol localization is supported by Reactome and AMBRA1 autophagy/mitophagy evidence. Reason: Cytosolic AMBRA1 complexes with dynein light chains and BECN1 are central to autophagy initiation models. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5678313 | ACCEPT | Summary: Cytosol localization is supported by Reactome and AMBRA1 autophagy/mitophagy evidence. Reason: Cytosolic AMBRA1 complexes with dynein light chains and BECN1 are central to autophagy initiation models. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5678315 | ACCEPT | Summary: Cytosol localization is supported by Reactome and AMBRA1 autophagy/mitophagy evidence. Reason: Cytosolic AMBRA1 complexes with dynein light chains and BECN1 are central to autophagy initiation models. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
| GO:0005737 cytoplasm | IDA PMID:17589504 Ambra1 regulates autophagy and development of the nervous sy... | ACCEPT | Summary: Cytoplasmic localization is supported for AMBRA1 autophagy functions. Reason: AMBRA1 cytoplasmic localization is consistent with its BECN1, dynein, and mitochondrial autophagy interactions. Supporting Evidence: file:human/AMBRA1/AMBRA1-notes.md AMBRA1 is a WD40-repeat autophagy regulator originally described as a BECN1-dependent positive regulator of autophagy. |
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Download this section (compressed HTML)Q: 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?
Suggested experts: GO autophagy editors, Proteostasis PN curators
Q: Should AMBRA1 autophagy-scaffold activity have a more specific molecular-function representation than generic protein binding while avoiding overstatement of direct catalytic activity?
Suggested experts: GO molecular-function editors, Autophagy domain experts
Q: 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?
Suggested experts: GO molecular-function editors, Ubiquitin-proteasome system curators
Experiment: 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.
Type: CMA reporter and rescue assay
Experiment: 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.
Type: structure-function rescue assay
Experiment: 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.
Type: structure-guided ubiquitylation and reporter assay
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