ATG9A is the only transmembrane protein of the core autophagy machinery. It is a multi-pass membrane protein that assembles into a homotrimer with a central, solvated pore connecting the two membrane leaflets, and this architecture gives it phospholipid scramblase activity. Small ATG9A-containing vesicles are delivered to the site of autophagosome formation, where ATG9A concentrates with ATG2 at the expanding edge of the phagophore; there it equilibrates across the bilayer the glycerophospholipids that ATG2 transfers from the endoplasmic reticulum into the cytosolic leaflet. Without that equilibration, lipid delivered by ATG2 would accumulate in one leaflet and membrane expansion would stall, which is why pore mutations that reduce scrambling produce markedly smaller autophagosomes. Between rounds of autophagy ATG9A resides in a cycling pool that moves through the trans-Golgi network, recycling endosomes and late endosomes, and its trafficking is directed by adaptors including the AP-4 complex.
Definition: The membrane system of a phagophore, comprising its two closely apposed lipid bilayers and the continuous rim that joins them, which expands by lipid acquisition and closes to form the double membrane of an autophagosome.
Justification: ATG9A is an integral multi-pass protein of this bilayer, not merely a resident of the structure, so GO:0061908 phagophore records its location less precisely than the evidence supports. GO has autophagosome membrane (GO:0000421) and omegasome membrane (GO:1903349) but no phagophore membrane, which is why such annotations went to GO:0034045 phagophore assembly site membrane - a term that asserts via bounding_layer_of a bounding membrane the PAS does not have (PMID:32025038). See GO issue #29437 recommendation R3. The sheet-versus-system question is unresolved upstream; this proposal takes the collective reading.
Parent term: membrane
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000407 phagophore assembly site | IBA GO_REF:0000033 | ACCEPT | Summary: ATG9A localizes to the phagophore assembly site, where it concentrates with ATG2 at the expanding rim. Reason: Core location, directly observed (IDA) and supported phylogenetically (IBA). This is the compartment term that GO:0034045 should have been. |
| GO:0017128 phospholipid scramblase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Lipid scramblase activity of the ATG9A homotrimer; the gene's core molecular function. Reason: ATG9A is a homotrimeric multi-pass membrane protein with a central pore that forms a path between the two membrane leaflets, and it scrambles phospholipids in vitro; pore mutations reduce scrambling and yield markedly smaller autophagosomes. This is the gene's defining biochemical activity and the reason it is the only transmembrane protein of the core autophagy machinery. Supporting Evidence: PMID:33106659 Mutations in the pore reduce scrambling activity and yield markedly smaller autophagosomes, indicating that lipid scrambling by ATG9A is essential for membrane expansion. |
| GO:0000423 mitophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Mitophagy, one selective autophagy route among several that use the core machinery. Reason: ATG9A contributes as core machinery rather than as a mitophagy-specific factor. Non-core, alongside reticulophagy. |
| GO:0061709 reticulophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Reticulophagy, another selective route served by the same core machinery. Reason: Same reasoning as mitophagy: participation is via the general phagophore machinery, not a receptor-level specificity. |
| GO:0034727 piecemeal microautophagy of the nucleus | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Piecemeal microautophagy of the nucleus, a yeast-defined process propagated phylogenetically. Reason: PMN is characterised in budding yeast at the nucleus-vacuole junction. Propagating it to human ATG9A by IBA asserts a process whose mammalian counterpart is not established. Over-annotated rather than removed, since the underlying machinery is genuinely shared. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH CONTEXT OR TISSUE MISMATCH Sources checked: SGD:S000002308 Β· ATG9 (Saccharomyces cerevisiae) SUPPORTS SOURCE BUT NOT TARGET Yeast Atg9 is genuinely required for piecemeal microautophagy of the nucleus, which proceeds at the nucleus-vacuole junction formed by Nvj1-Vac8. Humans have no vacuole and no characterised NVJ equivalent, so the process term does not transfer even though the Atg9 orthology is sound. PANTHER:PTN000315580 Β· ATG9 family node SUPPORTS SOURCE BUT NOT TARGET The node correctly groups ATG9 orthologs; the error is in propagating a fungal-specific process term across the whole node rather than in the grouping. |
| GO:0005776 autophagosome | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Autophagosome, parent of the autophagosome membrane term already supported. Reason: Less informative than GO:0000421 for a multi-pass membrane protein; retained as non-core. |
| GO:0034497 protein localization to phagophore assembly site | IBA GO_REF:0000033 | ACCEPT | Summary: ATG9A vesicles deliver protein and membrane to the phagophore assembly site. Reason: Consistent with the ATG9-vesicle seeding role; ATG9A cycles between the PAS and a cytoplasmic vesicle pool. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Endoplasmic reticulum membrane; ATG9A is present at the ER-phagophore interface where it receives lipid from ATG2. Reason: Supported by IDA and EXP. ATG9A concentrates with ATG2 at the expanding phagophore edge, which is apposed to the ER, so ER membrane is a genuine functional location. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Golgi apparatus, the uninformative parent of the trans-Golgi network and Golgi membrane terms the gene already carries. Reason: True but adds nothing over GO:0005802 and GO:0000139, both supported by direct evidence on this gene. Retained as a high-level default rather than removed. |
| GO:0006914 autophagy | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Autophagy, the broad parent of the specific assembly process this gene drives. Reason: GO:0000045 autophagosome assembly is the informative statement and is separately supported. The parent is retained as context. |
| GO:0017121 plasma membrane phospholipid scrambling | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Plasma membrane phospholipid scrambling, an electronic transfer of the scramblase activity to the wrong compartment. Reason: ATG9A's scramblase activity is exercised on autophagic membranes, where it equilibrates lipid delivered by ATG2, not at the plasma membrane. The molecular function GO:0017128 is correct and accepted; this process term attaches it to a compartment for which there is no evidence. Electronic only. |
| GO:0031902 late endosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Late endosome membrane, part of the ATG9A trafficking itinerary. Reason: Five independent EXP annotations plus IEA. ATG9A cycles through the endosomal system, and the membrane-level term is the informative one. |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: Mitochondrial membrane, an under-specified electronic annotation that does not say which mitochondrial membrane. Reason: Electronic only, and the under-specified member of its organelle triple. In this corpus SL-0171 mitochondrial membrane carries a 31% issue rate against 11% for the inner membrane and 7% for the matrix (projects/SL/SL-MITOCHONDRIA.md). ATG9A's relationship to mitochondria is via mitophagy rather than residence in a mitochondrial membrane, and no direct evidence places it in one. |
| GO:0034045 phagophore assembly site membrane | IEA GO_REF:0000044 | MODIFY | Summary: Phagophore assembly site membrane: the evidence describes ATG9A on the phagophore itself, not on a membrane bounding the assembly site. Reason: GO:0034045 asserts via bounding_layer_of that a membrane bounds the phagophore assembly site. The PAS is a liquid-like protein condensate with no bounding bilayer (PMID:32025038), and the term carries phagophore and isolation membrane as related synonyms of the distinct term GO:0061908 - see GO issue #29437 and projects/CONDENSATES/GO_0034045-annotation-audit.md. ATG9A is the emblematic case in that issue's section 5.4 triage: it colocalizes with ATG2 at the expanding edge of the isolation membrane. Moved to GO:0061908, the existing term those synonyms belong to. The precise destination is the phagophore membrane, proposed under proposed_new_terms, since ATG9A is an integral membrane protein of that bilayer rather than merely present at the structure. Proposed replacements: phagophore Supporting Evidence: PMID:33106658 Atg9 colocalizes with Atg2 at the expanding edge of the isolation membrane (IM), where Atg2 receives phospholipids from the endoplasmic reticulum (ER). |
| GO:0055038 recycling endosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Recycling endosome membrane; a documented ATG9A compartment and a proposed alternative membrane source for the phagophore. Reason: Supported by EXP and IDA. The recycling endosome is where mammalian phagophore precursors have been proposed to originate, so this is functionally relevant rather than incidental. |
| GO:0005515 protein binding | IPI PMID:19893488 Coordinated regulation of autophagy by p38alpha MAPK through... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from ten independent IPI experiments; uninformative as a function statement. Reason: Per project curation guidance, protein binding does not describe what the gene product does. The interactions behind these annotations are individually meaningful - ATG2A via the ATG9A C-terminus, AP4M1, ARFIP1/2, PI4K2A/PI4KB, ATG4A - and belong in the interaction record or as specific adaptor/tethering terms, not as a bare binding annotation. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from ten independent IPI experiments; uninformative as a function statement. Reason: Per project curation guidance, protein binding does not describe what the gene product does. The interactions behind these annotations are individually meaningful - ATG2A via the ATG9A C-terminus, AP4M1, ARFIP1/2, PI4K2A/PI4KB, ATG4A - and belong in the interaction record or as specific adaptor/tethering terms, not as a bare binding annotation. |
| GO:0005515 protein binding | IPI PMID:24603492 TBC1D5 and the AP2 complex regulate ATG9 trafficking and ini... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from ten independent IPI experiments; uninformative as a function statement. Reason: Per project curation guidance, protein binding does not describe what the gene product does. The interactions behind these annotations are individually meaningful - ATG2A via the ATG9A C-terminus, AP4M1, ARFIP1/2, PI4K2A/PI4KB, ATG4A - and belong in the interaction record or as specific adaptor/tethering terms, not as a bare binding annotation. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from ten independent IPI experiments; uninformative as a function statement. Reason: Per project curation guidance, protein binding does not describe what the gene product does. The interactions behind these annotations are individually meaningful - ATG2A via the ATG9A C-terminus, AP4M1, ARFIP1/2, PI4K2A/PI4KB, ATG4A - and belong in the interaction record or as specific adaptor/tethering terms, not as a bare binding annotation. |
| GO:0005515 protein binding | IPI PMID:31412244 TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes f... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from ten independent IPI experiments; uninformative as a function statement. Reason: Per project curation guidance, protein binding does not describe what the gene product does. The interactions behind these annotations are individually meaningful - ATG2A via the ATG9A C-terminus, AP4M1, ARFIP1/2, PI4K2A/PI4KB, ATG4A - and belong in the interaction record or as specific adaptor/tethering terms, not as a bare binding annotation. |
| GO:0005515 protein binding | IPI PMID:33436498 Cytoplasmic short linear motifs in ACE2 and integrin Ξ²(3) li... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from ten independent IPI experiments; uninformative as a function statement. Reason: Per project curation guidance, protein binding does not describe what the gene product does. The interactions behind these annotations are individually meaningful - ATG2A via the ATG9A C-terminus, AP4M1, ARFIP1/2, PI4K2A/PI4KB, ATG4A - and belong in the interaction record or as specific adaptor/tethering terms, not as a bare binding annotation. |
| GO:0005515 protein binding | IPI PMID:34799561 Large scale discovery of coronavirus-host factor protein int... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from ten independent IPI experiments; uninformative as a function statement. Reason: Per project curation guidance, protein binding does not describe what the gene product does. The interactions behind these annotations are individually meaningful - ATG2A via the ATG9A C-terminus, AP4M1, ARFIP1/2, PI4K2A/PI4KB, ATG4A - and belong in the interaction record or as specific adaptor/tethering terms, not as a bare binding annotation. |
| GO:0005515 protein binding | IPI PMID:37100772 Large-scale phage-based screening reveals extensive pan-vira... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from ten independent IPI experiments; uninformative as a function statement. Reason: Per project curation guidance, protein binding does not describe what the gene product does. The interactions behind these annotations are individually meaningful - ATG2A via the ATG9A C-terminus, AP4M1, ARFIP1/2, PI4K2A/PI4KB, ATG4A - and belong in the interaction record or as specific adaptor/tethering terms, not as a bare binding annotation. |
| GO:0005515 protein binding | IPI PMID:37219487 Large-scale phosphomimetic screening identifies phospho-modu... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from ten independent IPI experiments; uninformative as a function statement. Reason: Per project curation guidance, protein binding does not describe what the gene product does. The interactions behind these annotations are individually meaningful - ATG2A via the ATG9A C-terminus, AP4M1, ARFIP1/2, PI4K2A/PI4KB, ATG4A - and belong in the interaction record or as specific adaptor/tethering terms, not as a bare binding annotation. |
| GO:0000139 Golgi membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Golgi membrane, the membrane-level statement of the TGN pool. Reason: Directly observed; more informative than the bare Golgi apparatus parent, which is retained as non-core. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cytoplasm, a high-level default for a protein whose specific compartments are well established. Reason: Uninformative relative to the several specific membrane compartments annotated on this gene with direct evidence. |
| GO:0005776 autophagosome | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Autophagosome, parent of the autophagosome membrane term already supported. Reason: Less informative than GO:0000421 for a multi-pass membrane protein; retained as non-core. |
| GO:0060349 bone morphogenesis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Bone morphogenesis, an organismal phenotype inferred by similarity. Reason: ISS and IEA only. This is a developmental consequence of impaired autophagy in a specific tissue, several steps removed from the scramblase activity; it does not describe what the gene product does. |
| GO:0097060 synaptic membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Synaptic membrane, an electronic annotation reflecting neuronal ATG9A trafficking. Reason: ATG9A does traffic in neurons and at synapses, but this is a cell-type-specific instance of its general vesicular itinerary rather than a distinct function. Electronic only; kept as non-core. |
| GO:0097300 programmed necrotic cell death | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Programmed necrotic cell death, inferred by similarity only. Reason: ISS and IEA with no direct evidence on the human protein. Autophagy machinery influences cell-death outcomes downstream and pleiotropically; this is a phenotype of perturbing autophagy rather than a function of ATG9A. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:20124090 Atg9A protein, an autophagy-related membrane protein, is loc... | ACCEPT | Summary: Endoplasmic reticulum membrane; ATG9A is present at the ER-phagophore interface where it receives lipid from ATG2. Reason: Supported by IDA and EXP. ATG9A concentrates with ATG2 at the expanding phagophore edge, which is apposed to the ER, so ER membrane is a genuine functional location. |
| GO:0031902 late endosome membrane | EXP PMID:16940348 Starvation and ULK1-dependent cycling of mammalian Atg9 betw... | ACCEPT | Summary: Late endosome membrane, part of the ATG9A trafficking itinerary. Reason: Five independent EXP annotations plus IEA. ATG9A cycles through the endosomal system, and the membrane-level term is the informative one. |
| GO:0031902 late endosome membrane | EXP PMID:20124090 Atg9A protein, an autophagy-related membrane protein, is loc... | ACCEPT | Summary: Late endosome membrane, part of the ATG9A trafficking itinerary. Reason: Five independent EXP annotations plus IEA. ATG9A cycles through the endosomal system, and the membrane-level term is the informative one. |
| GO:0031902 late endosome membrane | EXP PMID:22456507 Dynamic and transient interactions of Atg9 with autophagosom... | ACCEPT | Summary: Late endosome membrane, part of the ATG9A trafficking itinerary. Reason: Five independent EXP annotations plus IEA. ATG9A cycles through the endosomal system, and the membrane-level term is the informative one. |
| GO:0031902 late endosome membrane | EXP PMID:32513819 A heterodimeric SNX4--SNX7 SNX-BAR autophagy complex coordin... | ACCEPT | Summary: Late endosome membrane, part of the ATG9A trafficking itinerary. Reason: Five independent EXP annotations plus IEA. ATG9A cycles through the endosomal system, and the membrane-level term is the informative one. |
| GO:0031902 late endosome membrane | EXP PMID:33468622 The phosphatidylinositol 3-phosphate-binding protein SNX4 co... | ACCEPT | Summary: Late endosome membrane, part of the ATG9A trafficking itinerary. Reason: Five independent EXP annotations plus IEA. ATG9A cycles through the endosomal system, and the membrane-level term is the informative one. |
| GO:0034045 phagophore assembly site membrane | EXP PMID:18936157 Kinase-inactivated ULK proteins inhibit autophagy via their ... | MODIFY | Summary: Phagophore assembly site membrane: the evidence describes ATG9A on the phagophore itself, not on a membrane bounding the assembly site. Reason: GO:0034045 asserts via bounding_layer_of that a membrane bounds the phagophore assembly site. The PAS is a liquid-like protein condensate with no bounding bilayer (PMID:32025038), and the term carries phagophore and isolation membrane as related synonyms of the distinct term GO:0061908 - see GO issue #29437 and projects/CONDENSATES/GO_0034045-annotation-audit.md. ATG9A is the emblematic case in that issue's section 5.4 triage: it colocalizes with ATG2 at the expanding edge of the isolation membrane. Moved to GO:0061908, the existing term those synonyms belong to. The precise destination is the phagophore membrane, proposed under proposed_new_terms, since ATG9A is an integral membrane protein of that bilayer rather than merely present at the structure. Proposed replacements: phagophore Supporting Evidence: PMID:33106658 Atg9 colocalizes with Atg2 at the expanding edge of the isolation membrane (IM), where Atg2 receives phospholipids from the endoplasmic reticulum (ER). |
| GO:0034045 phagophore assembly site membrane | EXP PMID:32073997 The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to media... | MODIFY | Summary: Phagophore assembly site membrane: the evidence describes ATG9A on the phagophore itself, not on a membrane bounding the assembly site. Reason: GO:0034045 asserts via bounding_layer_of that a membrane bounds the phagophore assembly site. The PAS is a liquid-like protein condensate with no bounding bilayer (PMID:32025038), and the term carries phagophore and isolation membrane as related synonyms of the distinct term GO:0061908 - see GO issue #29437 and projects/CONDENSATES/GO_0034045-annotation-audit.md. ATG9A is the emblematic case in that issue's section 5.4 triage: it colocalizes with ATG2 at the expanding edge of the isolation membrane. Moved to GO:0061908, the existing term those synonyms belong to. The precise destination is the phagophore membrane, proposed under proposed_new_terms, since ATG9A is an integral membrane protein of that bilayer rather than merely present at the structure. Proposed replacements: phagophore Supporting Evidence: PMID:33106658 Atg9 colocalizes with Atg2 at the expanding edge of the isolation membrane (IM), where Atg2 receives phospholipids from the endoplasmic reticulum (ER). |
| GO:0034045 phagophore assembly site membrane | EXP PMID:33106659 Structure, lipid scrambling activity and role in autophagoso... | MODIFY | Summary: Phagophore assembly site membrane: the evidence describes ATG9A on the phagophore itself, not on a membrane bounding the assembly site. Reason: GO:0034045 asserts via bounding_layer_of that a membrane bounds the phagophore assembly site. The PAS is a liquid-like protein condensate with no bounding bilayer (PMID:32025038), and the term carries phagophore and isolation membrane as related synonyms of the distinct term GO:0061908 - see GO issue #29437 and projects/CONDENSATES/GO_0034045-annotation-audit.md. ATG9A is the emblematic case in that issue's section 5.4 triage: it colocalizes with ATG2 at the expanding edge of the isolation membrane. Moved to GO:0061908, the existing term those synonyms belong to. The precise destination is the phagophore membrane, proposed under proposed_new_terms, since ATG9A is an integral membrane protein of that bilayer rather than merely present at the structure. Proposed replacements: phagophore Supporting Evidence: PMID:33106658 Atg9 colocalizes with Atg2 at the expanding edge of the isolation membrane (IM), where Atg2 receives phospholipids from the endoplasmic reticulum (ER). |
| GO:0055038 recycling endosome membrane | EXP PMID:22456507 Dynamic and transient interactions of Atg9 with autophagosom... | ACCEPT | Summary: Recycling endosome membrane; a documented ATG9A compartment and a proposed alternative membrane source for the phagophore. Reason: Supported by EXP and IDA. The recycling endosome is where mammalian phagophore precursors have been proposed to originate, so this is functionally relevant rather than incidental. |
| GO:0097300 programmed necrotic cell death | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Programmed necrotic cell death, inferred by similarity only. Reason: ISS and IEA with no direct evidence on the human protein. Autophagy machinery influences cell-death outcomes downstream and pleiotropically; this is a phenotype of perturbing autophagy rather than a function of ATG9A. |
| GO:0005739 mitochondrion | IDA PMID:34432599 C5orf51 is a component of the MON1-CCZ1 complex and controls... | KEEP AS NON CORE | Summary: Mitochondrion, observed directly but peripheral to the gene's core function. Reason: ATG9A engages mitochondria as autophagic cargo during mitophagy rather than residing there constitutively. Kept as non-core rather than removed, since the observation is direct. |
| GO:0005794 Golgi apparatus | IDA PMID:34432599 C5orf51 is a component of the MON1-CCZ1 complex and controls... | KEEP AS NON CORE | Summary: Golgi apparatus, the uninformative parent of the trans-Golgi network and Golgi membrane terms the gene already carries. Reason: True but adds nothing over GO:0005802 and GO:0000139, both supported by direct evidence on this gene. Retained as a high-level default rather than removed. |
| GO:0000045 autophagosome assembly | IMP PMID:29180427 AP-4 mediates export of ATG9A from the trans-Golgi network t... | ACCEPT | Summary: Autophagosome assembly is the core process ATG9A serves, by equilibrating newly delivered lipid across the growing bilayer. Reason: Core biological process, supported by multiple independent IMP and IDA annotations. ATG9A scramblase activity distributes the phospholipids delivered by ATG2 into the phagophore, which is the step that permits membrane expansion. |
| GO:0000045 autophagosome assembly | IDA PMID:29437695 SNX18 regulates ATG9A trafficking from recycling endosomes b... | ACCEPT | Summary: Autophagosome assembly is the core process ATG9A serves, by equilibrating newly delivered lipid across the growing bilayer. Reason: Core biological process, supported by multiple independent IMP and IDA annotations. ATG9A scramblase activity distributes the phospholipids delivered by ATG2 into the phagophore, which is the step that permits membrane expansion. |
| GO:0000045 autophagosome assembly | IDA PMID:32513819 A heterodimeric SNX4--SNX7 SNX-BAR autophagy complex coordin... | ACCEPT | Summary: Autophagosome assembly is the core process ATG9A serves, by equilibrating newly delivered lipid across the growing bilayer. Reason: Core biological process, supported by multiple independent IMP and IDA annotations. ATG9A scramblase activity distributes the phospholipids delivered by ATG2 into the phagophore, which is the step that permits membrane expansion. |
| GO:0000045 autophagosome assembly | IDA PMID:33468622 The phosphatidylinositol 3-phosphate-binding protein SNX4 co... | ACCEPT | Summary: Autophagosome assembly is the core process ATG9A serves, by equilibrating newly delivered lipid across the growing bilayer. Reason: Core biological process, supported by multiple independent IMP and IDA annotations. ATG9A scramblase activity distributes the phospholipids delivered by ATG2 into the phagophore, which is the step that permits membrane expansion. |
| GO:0000139 Golgi membrane | IDA PMID:27663665 A conserved glycine residue in the C-terminal region of huma... | ACCEPT | Summary: Golgi membrane, the membrane-level statement of the TGN pool. Reason: Directly observed; more informative than the bare Golgi apparatus parent, which is retained as non-core. |
| GO:0005515 protein binding | IPI PMID:29180427 AP-4 mediates export of ATG9A from the trans-Golgi network t... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from ten independent IPI experiments; uninformative as a function statement. Reason: Per project curation guidance, protein binding does not describe what the gene product does. The interactions behind these annotations are individually meaningful - ATG2A via the ATG9A C-terminus, AP4M1, ARFIP1/2, PI4K2A/PI4KB, ATG4A - and belong in the interaction record or as specific adaptor/tethering terms, not as a bare binding annotation. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:27316455 Molecular determinants that mediate the sorting of human ATG... | ACCEPT | Summary: Endoplasmic reticulum membrane; ATG9A is present at the ER-phagophore interface where it receives lipid from ATG2. Reason: Supported by IDA and EXP. ATG9A concentrates with ATG2 at the expanding phagophore edge, which is apposed to the ER, so ER membrane is a genuine functional location. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:27663665 A conserved glycine residue in the C-terminal region of huma... | ACCEPT | Summary: Endoplasmic reticulum membrane; ATG9A is present at the ER-phagophore interface where it receives lipid from ATG2. Reason: Supported by IDA and EXP. ATG9A concentrates with ATG2 at the expanding phagophore edge, which is apposed to the ER, so ER membrane is a genuine functional location. |
| GO:0005802 trans-Golgi network | IDA PMID:29180427 AP-4 mediates export of ATG9A from the trans-Golgi network t... | ACCEPT | Summary: Trans-Golgi network is a principal steady-state location of ATG9A between rounds of autophagy. Reason: Four independent IDA annotations, and UniProt records Golgi apparatus, trans-Golgi network membrane as an experimentally supported location. The TGN pool is where ATG9A resides when not engaged at the phagophore, so this is core to its trafficking cycle rather than incidental. |
| GO:0017128 phospholipid scramblase activity | IDA PMID:33106659 Structure, lipid scrambling activity and role in autophagoso... | ACCEPT | Summary: Lipid scramblase activity of the ATG9A homotrimer; the gene's core molecular function. Reason: ATG9A is a homotrimeric multi-pass membrane protein with a central pore that forms a path between the two membrane leaflets, and it scrambles phospholipids in vitro; pore mutations reduce scrambling and yield markedly smaller autophagosomes. This is the gene's defining biochemical activity and the reason it is the only transmembrane protein of the core autophagy machinery. Supporting Evidence: PMID:33106659 Mutations in the pore reduce scrambling activity and yield markedly smaller autophagosomes, indicating that lipid scrambling by ATG9A is essential for membrane expansion. |
| GO:0017128 phospholipid scramblase activity | IDA PMID:33850023 A model for a partnership of lipid transfer proteins and scr... | ACCEPT | Summary: Lipid scramblase activity of the ATG9A homotrimer; the gene's core molecular function. Reason: ATG9A is a homotrimeric multi-pass membrane protein with a central pore that forms a path between the two membrane leaflets, and it scrambles phospholipids in vitro; pore mutations reduce scrambling and yield markedly smaller autophagosomes. This is the gene's defining biochemical activity and the reason it is the only transmembrane protein of the core autophagy machinery. Supporting Evidence: PMID:33106659 Mutations in the pore reduce scrambling activity and yield markedly smaller autophagosomes, indicating that lipid scrambling by ATG9A is essential for membrane expansion. |
| GO:0055038 recycling endosome membrane | IDA PMID:29437695 SNX18 regulates ATG9A trafficking from recycling endosomes b... | ACCEPT | Summary: Recycling endosome membrane; a documented ATG9A compartment and a proposed alternative membrane source for the phagophore. Reason: Supported by EXP and IDA. The recycling endosome is where mammalian phagophore precursors have been proposed to originate, so this is functionally relevant rather than incidental. |
| GO:0060349 bone morphogenesis | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Bone morphogenesis, an organismal phenotype inferred by similarity. Reason: ISS and IEA only. This is a developmental consequence of impaired autophagy in a specific tissue, several steps removed from the scramblase activity; it does not describe what the gene product does. |
| GO:0005802 trans-Golgi network | IDA PMID:32073997 The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to media... | ACCEPT | Summary: Trans-Golgi network is a principal steady-state location of ATG9A between rounds of autophagy. Reason: Four independent IDA annotations, and UniProt records Golgi apparatus, trans-Golgi network membrane as an experimentally supported location. The TGN pool is where ATG9A resides when not engaged at the phagophore, so this is core to its trafficking cycle rather than incidental. |
| GO:0034045 phagophore assembly site membrane | TAS Reactome:R-HSA-9840807 | MODIFY | Summary: Phagophore assembly site membrane: the evidence describes ATG9A on the phagophore itself, not on a membrane bounding the assembly site. Reason: GO:0034045 asserts via bounding_layer_of that a membrane bounds the phagophore assembly site. The PAS is a liquid-like protein condensate with no bounding bilayer (PMID:32025038), and the term carries phagophore and isolation membrane as related synonyms of the distinct term GO:0061908 - see GO issue #29437 and projects/CONDENSATES/GO_0034045-annotation-audit.md. ATG9A is the emblematic case in that issue's section 5.4 triage: it colocalizes with ATG2 at the expanding edge of the isolation membrane. Moved to GO:0061908, the existing term those synonyms belong to. The precise destination is the phagophore membrane, proposed under proposed_new_terms, since ATG9A is an integral membrane protein of that bilayer rather than merely present at the structure. Proposed replacements: phagophore Supporting Evidence: PMID:33106658 Atg9 colocalizes with Atg2 at the expanding edge of the isolation membrane (IM), where Atg2 receives phospholipids from the endoplasmic reticulum (ER). |
| GO:0000045 autophagosome assembly | IMP PMID:22456507 Dynamic and transient interactions of Atg9 with autophagosom... | ACCEPT | Summary: Autophagosome assembly is the core process ATG9A serves, by equilibrating newly delivered lipid across the growing bilayer. Reason: Core biological process, supported by multiple independent IMP and IDA annotations. ATG9A scramblase activity distributes the phospholipids delivered by ATG2 into the phagophore, which is the step that permits membrane expansion. |
| GO:0000407 phagophore assembly site | IDA PMID:22456507 Dynamic and transient interactions of Atg9 with autophagosom... | ACCEPT | Summary: ATG9A localizes to the phagophore assembly site, where it concentrates with ATG2 at the expanding rim. Reason: Core location, directly observed (IDA) and supported phylogenetically (IBA). This is the compartment term that GO:0034045 should have been. |
| GO:0000421 autophagosome membrane | IDA NOT PMID:22456507 Dynamic and transient interactions of Atg9 with autophagosom... | ACCEPT | Summary: Autophagosome membrane; ATG9A-containing membrane is incorporated into the forming autophagosome. Reason: Directly observed, and recorded by UniProt as an experimentally supported location. |
| GO:0005770 late endosome | IDA PMID:22456507 Dynamic and transient interactions of Atg9 with autophagosom... | KEEP AS NON CORE | Summary: Late endosome, the parent of the membrane term already supported on this gene. Reason: Less informative than GO:0031902, which carries the direct evidence. Kept as non-core. |
| GO:0005802 trans-Golgi network | IDA PMID:22456507 Dynamic and transient interactions of Atg9 with autophagosom... | ACCEPT | Summary: Trans-Golgi network is a principal steady-state location of ATG9A between rounds of autophagy. Reason: Four independent IDA annotations, and UniProt records Golgi apparatus, trans-Golgi network membrane as an experimentally supported location. The TGN pool is where ATG9A resides when not engaged at the phagophore, so this is core to its trafficking cycle rather than incidental. |
| GO:0055037 recycling endosome | IDA PMID:22456507 Dynamic and transient interactions of Atg9 with autophagosom... | KEEP AS NON CORE | Summary: Recycling endosome, parent of the membrane term already supported. Reason: Less informative than GO:0055038; retained as non-core. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: Bare membrane, from a high-throughput dataset; uninformative for a protein with many specific membrane locations. Reason: Same shape as the SL project's pattern A (bare parent retained alongside specific children), though the source here is a proteomics dataset rather than GO_REF:0000044. ATG9A carries GO:0005789, GO:0000139, GO:0031902, GO:0055038 and GO:0000421, all from direct evidence. The bare membrane parent adds no information over any of them and is not false, only empty. See projects/SL.md for the pattern. |
| GO:0005768 endosome | IDA PMID:23093945 Regulation of ATG4B stability by RNF5 limits basal levels of... | KEEP AS NON CORE | Summary: Endosome, the broad parent of the late and recycling endosome terms this gene already carries. Reason: True but uninformative given the more specific endosomal terms present with direct evidence. |
| GO:0005802 trans-Golgi network | IDA PMID:23093945 Regulation of ATG4B stability by RNF5 limits basal levels of... | ACCEPT | Summary: Trans-Golgi network is a principal steady-state location of ATG9A between rounds of autophagy. Reason: Four independent IDA annotations, and UniProt records Golgi apparatus, trans-Golgi network membrane as an experimentally supported location. The TGN pool is where ATG9A resides when not engaged at the phagophore, so this is core to its trafficking cycle rather than incidental. |
| GO:0000045 autophagosome assembly | IMP PMID:15755735 Endothelial nitric-oxide synthase antisense (NOS3AS) gene en... | ACCEPT | Summary: Autophagosome assembly is the core process ATG9A serves, by equilibrating newly delivered lipid across the growing bilayer. Reason: Core biological process, supported by multiple independent IMP and IDA annotations. ATG9A scramblase activity distributes the phospholipids delivered by ATG2 into the phagophore, which is the step that permits membrane expansion. |
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Download this section (compressed HTML)Q: Does ATG9A scramblase activity have lipid-headgroup preference in vivo, or is it non-selective as the in-vitro liposome assays suggest?
Q: What fraction of the final autophagosomal surface derives from ATG9A-vesicle membrane delivered at the assembly site, versus lipid transferred through ATG2?
Experiment: Reconstitute ATG2-mediated transfer into proteoliposomes bearing wild-type or pore-mutant ATG9A and measure net bilayer expansion and transbilayer distribution simultaneously.
Hypothesis: ATG9A scrambling and ATG2 transfer are kinetically coupled, so that slowing one limits the other.
Type: in vitro reconstitution
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