id: Q2TAZ0 gene_symbol: ATG2A product_type: PROTEIN status: COMPLETE tags: - proteostasis - pn taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ATG2A is a large autophagy-related lipid transfer protein that acts at ER-phagophore contact sites during autophagosome biogenesis. It forms functional assemblies with WIPI/Atg18-family PI3P effectors and ATG9A-containing membranes, tethers membrane compartments, and transfers glycerophospholipids to support phagophore expansion. ATG2A also associates with lipid droplets and ER-mitochondria contact sites, but its principal characterized role is membrane supply for autophagosome formation. alternative_products: - name: '1' id: Q2TAZ0-1 - name: '2' id: Q2TAZ0-3 sequence_note: VSP_030515 - name: '3' id: Q2TAZ0-4 sequence_note: VSP_030510, VSP_030516 - name: '4' id: Q2TAZ0-5 sequence_note: VSP_030511, VSP_030512 existing_annotations: - term: id: GO:0000407 label: phagophore assembly site evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: ATG2A acts at the phagophore assembly site during autophagosome biogenesis. action: ACCEPT reason: >- Accept as a core location/context. Human ATG2A localizes to ER-phagophore/autophagophore contact sites and functions in lipid transfer during phagophore expansion; the IBA assignment is consistent with direct human evidence and the conserved ATG2/Atg18 autophagy module. additional_reference_ids: - PMID:30952800 - PMID:31271352 - file:human/ATG2A/ATG2A-uniprot.txt supported_by: - reference_id: PMID:30952800 supporting_text: localization of human ATG2A to contact sites between the ER and the autophagophore - reference_id: file:human/ATG2A/ATG2A-uniprot.txt supporting_text: Localizes to endoplasmic reticulum-autophagosome contact sites. - term: id: GO:0000422 label: autophagy of mitochondrion evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Mitophagy is too cargo-specific for ATG2A based on the available human evidence. action: MODIFY reason: >- ATG2A is required for phagophore expansion and can be recruited to ER-mitochondria contact sites, but the cached human ATG2A evidence supports general autophagosome assembly rather than an ATG2A-specific mitophagy cargo-selection function. The safer PN interpretation is core autophagosome biogenesis, not cargo-specific mitochondrial autophagy. proposed_replacement_terms: - id: GO:0000045 label: autophagosome assembly additional_reference_ids: - PMID:30952800 - PMID:31412244 supported_by: - reference_id: PMID:31412244 supporting_text: mammalian Atg2A/B functions at the membrane expansion step during autophagosome biogenesis - reference_id: PMID:31412244 supporting_text: Atg2A translocates to the autophagosome formation site at the ER-mitochondria contact site - term: id: GO:0061908 label: phagophore evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: ATG2A is active at the expanding phagophore. action: ACCEPT reason: >- Accept as a core cellular context. ATG2A is placed at the phagophore/ER interface and promotes phagophore expansion by lipid transfer and tethering. additional_reference_ids: - PMID:31271352 - file:human/ATG2A/ATG2A-uniprot.txt supported_by: - reference_id: PMID:31271352 supporting_text: we place the ATG2-WIPI complex between the ER and the phagophore edge - reference_id: file:human/ATG2A/ATG2A-uniprot.txt supporting_text: Tethers the edge of the isolation membrane (IM) to the endoplasmic reticulum (ER) - term: id: GO:0000425 label: pexophagy evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Pexophagy over-specifies the supported ATG2A process role. action: MODIFY reason: >- ATG2A is core autophagosome-biogenesis machinery. The available human evidence does not establish an ATG2A-specific role in peroxisome cargo recognition or peroxisome-selective autophagy, so this cargo-specific IBA should be generalized. proposed_replacement_terms: - id: GO:0000045 label: autophagosome assembly additional_reference_ids: - PMID:30952800 - PMID:31271352 supported_by: - reference_id: PMID:30952800 supporting_text: protein-mediated lipid transfer across contact sites is a principal contributor to autophagosome formation - reference_id: PMID:31271352 supporting_text: ATG2-mediated transfer of lipids from the ER to the phagophore enables phagophore expansion - term: id: GO:0043495 label: protein-membrane adaptor activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: ATG2A has a core membrane-adaptor/tethering role at ER-phagophore contact sites. action: ACCEPT reason: >- Accept as a core molecular function. ATG2A couples WIPI/Atg18-family PI3P effectors, ATG9A-containing membranes, and ER/phagophore membranes in a lipid-transfer assembly. This term captures the adaptor/tether aspect of the function alongside the more direct lipid transfer activity term. additional_reference_ids: - PMID:31271352 - PMID:31412244 - PMID:39174844 supported_by: - reference_id: PMID:31271352 supporting_text: ATG2 stably tethers two membranes and transfers lipids between them - reference_id: PMID:39174844 supporting_text: ATG2A tethers lipid vesicles at different orientations - term: id: GO:0061723 label: glycophagy evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Glycophagy is too cargo-specific for the reviewed ATG2A evidence. action: MODIFY reason: >- The evidence supports ATG2A as general phagophore expansion machinery. No cached human evidence shows that ATG2A specifically recognizes glycogen cargo or has a glycophagy-selective role independent of its core autophagosome-assembly function. proposed_replacement_terms: - id: GO:0000045 label: autophagosome assembly additional_reference_ids: - PMID:30952800 - PMID:31271352 supported_by: - reference_id: PMID:30952800 supporting_text: fully sufficient to rescue blocked autophagosome biogenesis in ATG2A/ATG2B KO cells - reference_id: PMID:31271352 supporting_text: ATG2-mediated transfer of lipids from the ER to the phagophore enables phagophore expansion - term: id: GO:0032266 label: phosphatidylinositol-3-phosphate binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: PI3P-associated recruitment is supported, but direct ATG2A PI3P binding is not established. action: MARK_AS_OVER_ANNOTATED reason: >- Human ATG2A is recruited to PI3P-rich phagophore membranes through WIPI/Atg18-family effectors. The accessible evidence supports WIPI-mediated association with PI3P-containing membranes rather than ATG2A itself independently enabling phosphatidylinositol-3-phosphate binding. additional_reference_ids: - PMID:31271352 - PMID:32483132 supported_by: - reference_id: PMID:31271352 supporting_text: WIPI4 and WIPI1 associate ATG2A stably to PI3P-containing vesicles - reference_id: PMID:32483132 supporting_text: WIPI proteins tend to recognize phosphoinositides and the WIR-peptide simultaneously - term: id: GO:0034727 label: piecemeal microautophagy of the nucleus evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Nucleophagy/PMN over-specifies the conserved ATG2A autophagy role. action: MODIFY reason: >- The annotation projects a cargo- and pathway-specific yeast selective-autophagy process to human ATG2A. Human ATG2A evidence supports autophagosome biogenesis through lipid transfer, not a direct ATG2A-specific role in piecemeal nuclear microautophagy. proposed_replacement_terms: - id: GO:0000045 label: autophagosome assembly additional_reference_ids: - PMID:30952800 - PMID:31271352 supported_by: - reference_id: PMID:30952800 supporting_text: lipid transfer across contact sites is a principal contributor to autophagosome formation - reference_id: PMID:31271352 supporting_text: transfer of ER lipids to the phagophore, driving phagophore expansion - term: id: GO:0061709 label: reticulophagy evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Reticulophagy is plausible pathway context but not an ATG2A-specific cargo claim. action: MODIFY reason: >- ATG2A functions at ER-phagophore contact sites, but that does not by itself establish a selective ER-autophagy role for ATG2A. The conservative replacement is the general autophagosome-assembly process supported by direct lipid-transfer and rescue data. proposed_replacement_terms: - id: GO:0000045 label: autophagosome assembly additional_reference_ids: - PMID:30952800 - PMID:31271352 supported_by: - reference_id: PMID:30952800 supporting_text: operating at the ER-autophagosome interface - reference_id: PMID:31271352 supporting_text: ATG2-mediated transfer of lipids from the ER to the phagophore - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: ER membrane localization is supported and central to ATG2A function. action: ACCEPT reason: >- Accept. UniProt subcellular-location mapping agrees with direct human evidence placing ATG2A at ER-autophagosome/phagophore contact sites, where it mediates lipid transfer from ER-associated donor membranes. additional_reference_ids: - PMID:30952800 - file:human/ATG2A/ATG2A-uniprot.txt supported_by: - reference_id: PMID:30952800 supporting_text: operating at the ER-autophagosome interface - reference_id: file:human/ATG2A/ATG2A-uniprot.txt supporting_text: Endoplasmic reticulum membrane - term: id: GO:0005811 label: lipid droplet evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Lipid-droplet association is supported but secondary to the core autophagosome-biogenesis role. action: KEEP_AS_NON_CORE reason: >- Keep as non-core. ATG2A has a documented lipid-droplet association and affects lipid-droplet morphology, but the PN-relevant core function is ER/phagophore lipid transfer for autophagosome assembly. additional_reference_ids: - file:human/ATG2A/ATG2A-uniprot.txt supported_by: - reference_id: file:human/ATG2A/ATG2A-uniprot.txt supporting_text: Also regulates lipid droplets morphology and distribution within the cell - term: id: GO:0006914 label: autophagy evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: Autophagy is correct but too broad for the reviewed ATG2A process. action: MODIFY reason: >- ATG2A is not merely associated with generic autophagy; direct experiments support a more specific role in autophagosome assembly through phagophore expansion and lipid transfer. proposed_replacement_terms: - id: GO:0000045 label: autophagosome assembly additional_reference_ids: - PMID:30952800 - PMID:31271352 supported_by: - reference_id: PMID:30952800 supporting_text: lipid transfer across contact sites is a principal contributor to autophagosome formation - reference_id: PMID:31271352 supporting_text: ATG2-mediated transfer of lipids from the ER to the phagophore enables phagophore expansion - term: id: GO:0034045 label: phagophore assembly site membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: ATG2A localizes to the phagophore assembly site membrane. action: ACCEPT reason: >- Accept. This location is supported by UniProt subcellular mapping and direct imaging/biochemical evidence placing ATG2A at the ER-phagophore edge. additional_reference_ids: - PMID:30952800 - PMID:31271352 - file:human/ATG2A/ATG2A-uniprot.txt supported_by: - reference_id: PMID:31271352 supporting_text: between the ER and the phagophore edge - reference_id: file:human/ATG2A/ATG2A-uniprot.txt supporting_text: Preautophagosomal structure membrane - term: id: GO:0120009 label: intermembrane lipid transfer evidence_type: IEA original_reference_id: GO_REF:0000108 qualifier: involved_in review: summary: ATG2A mediates intermembrane lipid transfer during phagophore expansion. action: ACCEPT reason: >- Accept as a core biological process. The logical inference from lipid transfer activity is directly consistent with in vitro lipid-transfer assays, structural work, and cellular rescue data. additional_reference_ids: - PMID:30952800 - PMID:31271352 - PMID:39174844 supported_by: - reference_id: PMID:30952800 supporting_text: ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro - reference_id: PMID:39174844 supporting_text: mediating lipid transfer and re-equilibration between membranes for autophagosome formation - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20562859 qualifier: enables review: summary: Large-scale interaction evidence is real but generic protein binding is not informative. action: MARK_AS_OVER_ANNOTATED reason: >- The Behrends et al. autophagy interaction network places ATG2A among ATG8/WIPI-associated autophagy proteins, but GO:0005515 does not capture ATG2A's actual molecular function. The informative functions are lipid transfer, membrane tether/adaptor activity, and ATG2-WIPI/Atg18 complex membership. additional_reference_ids: - PMID:20562859 - PMID:31271352 supported_by: - reference_id: PMID:20562859 supporting_text: a network of 751 interactions among 409 candidate interacting proteins - reference_id: PMID:31271352 supporting_text: ATG2 stably tethers two membranes and transfers lipids between them - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31412244 qualifier: enables review: summary: ATG2A interactions with TOM40, ATG9A, and WIPI4 are functional context, not generic MF. action: MARK_AS_OVER_ANNOTATED reason: >- The interactions in this study are biologically meaningful for MAM recruitment and phagophore growth, but generic protein binding should not be retained as the functional statement. The better-curated assertions are organelle membrane contact site, autophagosome assembly, and lipid-transfer/adaptor roles. additional_reference_ids: - PMID:31412244 supported_by: - reference_id: PMID:31412244 supporting_text: Atg2A directly interacts with Atg9A at the MAM to promote phagophore growth - reference_id: PMID:31412244 supporting_text: TOM70-TOM40 complex recruits Atg2A to the MAM - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: High-throughput binary interactome protein binding is not informative for ATG2A function. action: MARK_AS_OVER_ANNOTATED reason: >- The binary interactome row does not add a mechanistic ATG2A function beyond generic protein binding and is not central to the autophagy/lipid-transfer evidence. It should not be treated as a core MF. additional_reference_ids: - PMID:32296183 supported_by: - reference_id: PMID:32296183 supporting_text: A reference map of the human binary protein interactome - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32483132 qualifier: enables review: summary: WIPI3/WIPI4 binding is specific evidence for the ATG2-WIPI/Atg18 complex, not generic binding. action: MARK_AS_OVER_ANNOTATED reason: >- This structural evidence supports a specific WIR-mediated association of ATG2A with WIPI beta-propellers, not generic protein binding as a useful molecular-function statement. Because GO:0062079 is a cellular-component term, the complex context is captured separately as a NEW annotation rather than as a replacement for this MF row. additional_reference_ids: - PMID:32483132 - file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml supported_by: - reference_id: PMID:32483132 supporting_text: WIPI4 forms a complex with ATG2A/B - reference_id: PMID:32483132 supporting_text: disrupt the interactions between WIPI3/4 and ATG2A and impair the ATG2A-mediated autophagic process - term: id: GO:0010508 label: positive regulation of autophagy evidence_type: IMP original_reference_id: PMID:32483132 qualifier: involved_in review: summary: ATG2A-WIPI disruption impairs autophagy, but ATG2A is core assembly machinery rather than only a regulator. action: MODIFY reason: >- The evidence shows that disrupting ATG2A-WIPI interactions impairs the ATG2A-mediated autophagic process. For ATG2A itself, the more direct process term is autophagosome assembly. proposed_replacement_terms: - id: GO:0000045 label: autophagosome assembly additional_reference_ids: - PMID:32483132 - PMID:31271352 supported_by: - reference_id: PMID:32483132 supporting_text: impair the ATG2A-mediated autophagic process - reference_id: PMID:31271352 supporting_text: Direct tethering of the ER and the phagophore edge by the ATG2-WIPI complex - term: id: GO:0120013 label: lipid transfer activity evidence_type: IMP original_reference_id: PMID:39174844 qualifier: enables review: summary: Structural data support ATG2A lipid transfer activity with ATG9A/WIPI4 complexes. action: ACCEPT reason: >- Accept as core molecular function. Structural and mechanistic evidence supports ATG2A as a lipid-transfer protein whose cavity and ATG9A/WIPI4-associated assemblies mediate lipid transfer during autophagosome formation. additional_reference_ids: - PMID:39174844 - PMID:30952800 - PMID:31271352 supported_by: - reference_id: PMID:39174844 supporting_text: Structural basis for lipid transfer by the ATG2A-ATG9A complex - reference_id: PMID:39174844 supporting_text: human ATG2A in complex with WD-repeat protein interacting with phosphoinositides 4 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: EXP original_reference_id: PMID:30952800 qualifier: located_in review: summary: Direct evidence places ATG2A at the ER/autophagosome interface. action: ACCEPT reason: >- Accept. This experimentally supported location is central to ATG2A's lipid-transfer function during phagophore expansion. additional_reference_ids: - PMID:30952800 - file:human/ATG2A/ATG2A-uniprot.txt supported_by: - reference_id: PMID:30952800 supporting_text: operating at the ER-autophagosome interface - reference_id: file:human/ATG2A/ATG2A-uniprot.txt supporting_text: Endoplasmic reticulum membrane - term: id: GO:0005811 label: lipid droplet evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Lipid-droplet localization is supported by homology/UniProt but is non-core for this review. action: KEEP_AS_NON_CORE reason: >- Keep as non-core. ATG2-family lipid-droplet association is compatible with UniProt, but the core human ATG2A role for this PN-focused review is lipid transfer at ER/phagophore contact sites. additional_reference_ids: - file:human/ATG2A/ATG2A-uniprot.txt supported_by: - reference_id: file:human/ATG2A/ATG2A-uniprot.txt supporting_text: Lipid droplet - term: id: GO:0034045 label: phagophore assembly site membrane evidence_type: EXP original_reference_id: PMID:30952800 qualifier: located_in review: summary: Direct experimental evidence supports ATG2A at the phagophore assembly site membrane. action: ACCEPT reason: >- Accept as a core location. ATG2A is positioned at ER-phagophore contact sites where lipid transfer supports phagophore expansion. additional_reference_ids: - PMID:30952800 - PMID:31271352 supported_by: - reference_id: PMID:30952800 supporting_text: contact sites between the ER and the autophagophore - reference_id: PMID:31271352 supporting_text: we place the ATG2-WIPI complex between the ER and the phagophore edge - term: id: GO:0044232 label: organelle membrane contact site evidence_type: IDA original_reference_id: PMID:30952800 qualifier: is_active_in review: summary: ATG2A is active at organelle membrane contact sites during autophagosome formation. action: ACCEPT reason: >- Accept. ATG2A is a contact-site lipid-transfer protein, with direct evidence for ER-autophagophore localization and functional lipid transfer across membranes. additional_reference_ids: - PMID:30952800 - PMID:31271352 supported_by: - reference_id: PMID:30952800 supporting_text: protein-mediated lipid transfer across contact sites is a principal contributor - reference_id: PMID:31271352 supporting_text: ATG2 stably tethers two membranes and transfers lipids between them - term: id: GO:0120013 label: lipid transfer activity evidence_type: IDA original_reference_id: PMID:30952800 qualifier: enables review: summary: Direct biochemical evidence supports ATG2A lipid transfer activity. action: ACCEPT reason: >- Accept as core molecular function. Purified human ATG2A binds multiple glycerophospholipids and transfers lipids between membranes in vitro, and lipid-transfer-competent ATG2A fragments rescue autophagosome biogenesis. additional_reference_ids: - PMID:30952800 - PMID:31271352 supported_by: - reference_id: PMID:30952800 supporting_text: ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro - reference_id: PMID:30952800 supporting_text: fully sufficient to rescue blocked autophagosome biogenesis in ATG2A/ATG2B KO cells - term: id: GO:0120013 label: lipid transfer activity evidence_type: IDA original_reference_id: PMID:31271352 qualifier: enables review: summary: ATG2A lipid transfer activity is directly demonstrated and WIPI-facilitated. action: ACCEPT reason: >- Accept as core molecular function. This study directly demonstrates human ATG2A lipid transfer, membrane tethering, and WIPI-enhanced association with PI3P-containing membranes. additional_reference_ids: - PMID:31271352 - PMID:30952800 supported_by: - reference_id: PMID:31271352 supporting_text: human ATG2A is a lipid transfer protein - reference_id: PMID:31271352 supporting_text: WIPI proteins can facilitate ATG2A-mediated lipid transfer - term: id: GO:2000786 label: positive regulation of autophagosome assembly evidence_type: IDA original_reference_id: PMID:30952800 qualifier: involved_in review: summary: ATG2A directly participates in autophagosome assembly rather than only regulating it. action: MODIFY reason: >- ATG2A lipid transfer supplies membrane for phagophore expansion, making autophagosome assembly the more direct process term. The regulation term is directionally true but less precise for a core autophagy machinery component. proposed_replacement_terms: - id: GO:0000045 label: autophagosome assembly additional_reference_ids: - PMID:30952800 supported_by: - reference_id: PMID:30952800 supporting_text: protein-mediated lipid transfer across contact sites is a principal contributor to autophagosome formation - reference_id: PMID:30952800 supporting_text: rescue blocked autophagosome biogenesis in ATG2A/ATG2B KO cells - term: id: GO:2000786 label: positive regulation of autophagosome assembly evidence_type: IDA original_reference_id: PMID:31271352 qualifier: involved_in review: summary: WIPI-facilitated ATG2A lipid transfer supports autophagosome assembly. action: MODIFY reason: >- The direct functional role is phagophore expansion/autophagosome assembly via lipid transfer. Use autophagosome assembly rather than a regulation term for this core machinery activity. proposed_replacement_terms: - id: GO:0000045 label: autophagosome assembly additional_reference_ids: - PMID:31271352 supported_by: - reference_id: PMID:31271352 supporting_text: transfer of ER lipids to the phagophore, driving phagophore expansion - reference_id: PMID:31271352 supporting_text: WIPI proteins can facilitate ATG2A-mediated lipid transfer - term: id: GO:0000045 label: autophagosome assembly evidence_type: IMP original_reference_id: PMID:28561066 qualifier: involved_in review: summary: ATG2A is a core autophagosome-assembly factor. action: ACCEPT reason: >- Accept as core process. WIPI4-ATG2 translocates to nascent autophagosomes and later studies show ATG2A lipid transfer and tethering drive phagophore expansion. additional_reference_ids: - PMID:28561066 - PMID:30952800 - PMID:31271352 supported_by: - reference_id: PMID:28561066 supporting_text: WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes - reference_id: PMID:30952800 supporting_text: protein-mediated lipid transfer across contact sites is a principal contributor to autophagosome formation - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28561066 qualifier: enables review: summary: WIPI4 interaction should be represented as ATG2-WIPI/Atg18 complex context, not generic binding. action: MARK_AS_OVER_ANNOTATED reason: >- The biologically meaningful claim is ATG2A association with WIPI4/WDR45 in the autophagy machinery. Generic protein binding is over-annotated for this evidence, and the GO:0062079 cellular-component complex context is captured separately as a NEW annotation rather than as a replacement for this MF row. additional_reference_ids: - PMID:28561066 - PMID:31271352 - file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml supported_by: - reference_id: PMID:28561066 supporting_text: WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex - reference_id: PMID:31271352 supporting_text: we place the ATG2-WIPI complex between the ER and the phagophore edge - term: id: GO:0062079 label: ATG2-ATG18 complex evidence_type: IDA original_reference_id: PMID:31271352 qualifier: part_of review: summary: The PN-projected ATG2-ATG18 complex term is a conservative, supported component annotation. action: NEW reason: >- The Proteostasis PN projection proposes GO:0062079 for the ATG2-WIPI complex component bucket. This is more precise than the existing phagophore assembly site locations and is supported by human ATG2A evidence showing ATG2-WIPI complexes at the ER-phagophore edge. The GO term uses the yeast Atg18 name, but mammalian WIPI proteins are Atg18-family PROPPINs, so this is a reasonable component-level propagation; it should not be expanded into cargo-specific selective-autophagy process annotations. additional_reference_ids: - PMID:31271352 - PMID:32483132 - PMID:39174844 - file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv supported_by: - reference_id: PMID:31271352 supporting_text: we place the ATG2-WIPI complex between the ER and the phagophore edge - reference_id: PMID:32483132 supporting_text: WIPI4 forms a complex with ATG2A/B - reference_id: file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml supporting_text: The GO ATG2-ATG18 complex term is the closest component-level target. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - 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: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:0000108 title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links findings: [] - id: PMID:20562859 title: Network organization of the human autophagy system. findings: - statement: Large-scale autophagy interaction network places ATG2A in autophagy-associated interaction context. supporting_text: a network of 751 interactions among 409 candidate interacting proteins - id: PMID:28561066 title: WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. findings: - statement: WIPI4-ATG2 translocates to nascent autophagosomes. supporting_text: WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes - id: PMID:30952800 title: ATG2 transports lipids to promote autophagosome biogenesis. findings: - statement: ATG2A transfers glycerophospholipids and supports autophagosome biogenesis. supporting_text: ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro - statement: ATG2A acts at ER-autophagosome contact sites. supporting_text: operating at the ER-autophagosome interface - id: PMID:31271352 title: The autophagic membrane tether ATG2A transfers lipids between membranes. findings: - statement: Human ATG2A is a lipid transfer protein. supporting_text: human ATG2A is a lipid transfer protein - statement: ATG2-WIPI complex acts between ER and phagophore edge. supporting_text: we place the ATG2-WIPI complex between the ER and the phagophore edge - id: PMID:31412244 title: TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes for Phagophore Expansion. findings: - statement: ATG2A/B loss impairs phagophore expansion. supporting_text: mammalian Atg2A/B functions at the membrane expansion step during autophagosome biogenesis - statement: Atg2A interacts with ATG9A at mitochondria-associated ER membranes. supporting_text: Atg2A directly interacts with Atg9A at the MAM to promote phagophore growth - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: - statement: Binary interactome evidence is generic interaction context. supporting_text: A reference map of the human binary protein interactome - id: PMID:32483132 title: Multi-site-mediated entwining of the linear WIR-motif around WIPI beta-propellers for autophagy. findings: - statement: WIPI proteins bind the ATG2A WIR motif and support ATG2A-mediated autophagy. supporting_text: WIPI4 forms a complex with ATG2A/B - id: PMID:39174844 title: Structural basis for lipid transfer by the ATG2A-ATG9A complex. findings: - statement: Structural data support ATG2A-ATG9A/WIPI4 lipid-transfer assemblies. supporting_text: Structural basis for lipid transfer by the ATG2A-ATG9A complex - id: PMID:38622126 title: ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores. findings: - statement: >- ANKFY1 is an endosome-localized, FYVE-domain ATG2A-binding protein that binds PI3P and enhances ATG2A-mediated lipid transfer between PI3P-containing liposomes, supporting endosome-to-phagophore lipid donation; ANKFY1 depletion phenocopies ATG2A/B loss. - id: PMID:37938170 title: ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A. full_text_unavailable: true findings: - statement: >- ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A and can form a heteromeric complex with ATG2A, consistent with ATG2A lipid transfer being coupled to ATG9-family scramblase activity. - id: PMID:37796195 title: Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy. full_text_unavailable: true findings: - statement: >- Lysosome damage induces non-canonical autophagy (CASM) and promotes ATG2/ATG8 engagement via an ATG2 LIR-dependent mode; the robustly demonstrated interaction was ATG2B-LC3A, with a proposed role in lysosome repair (ATG2A-specific contribution inferred rather than directly established). - id: PMID:38294121 title: Exploring the ATG9A interactome uncovers interaction with VPS13A. full_text_unavailable: true findings: - statement: >- ATG9A acts as a lipid scramblase whose function is thought to require interaction with the lipid transfer protein ATG2A; ATG9A and ATG2A are proposed to function together to expand the growing autophagosome, and ATG9A forms a distinct complex with VPS13A separate from the ATG9A-ATG2A complex. - id: file:human/ATG2A/ATG2A-uniprot.txt title: UniProtKB record for human ATG2A findings: - statement: UniProt summarizes ATG2A as a lipid transfer protein involved in autophagosome assembly. supporting_text: Lipid transfer protein involved in autophagosome assembly - id: file:human/ATG2A/ATG2A-goa.tsv title: GOA annotations fetched for human ATG2A findings: [] - id: file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml title: Proteostasis Network autophagy-lysosome pathway mappings findings: - statement: PN mapping treats the ATG2-WIPI bucket as the ATG2-ATG18 complex. supporting_text: The GO ATG2-ATG18 complex term is the closest component-level target. - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv title: Proteostasis Network projected candidate GO additions findings: - statement: ATG2A was projected to GO:0062079 ATG2-ATG18 complex. supporting_text: ATG2A was projected to GO:0062079 ATG2-ATG18 complex in the PN candidate additions table. core_functions: - description: >- ATG2A is a high-capacity glycerophospholipid transfer protein that tethers donor and acceptor membranes at ER-phagophore contact sites and supplies lipids for phagophore expansion during autophagosome assembly. molecular_function: id: GO:0120013 label: lipid transfer activity directly_involved_in: - id: GO:0120009 label: intermembrane lipid transfer - id: GO:0000045 label: autophagosome assembly locations: - id: GO:0044232 label: organelle membrane contact site - id: GO:0034045 label: phagophore assembly site membrane - id: GO:0005789 label: endoplasmic reticulum membrane supported_by: - reference_id: PMID:30952800 supporting_text: ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro - reference_id: PMID:31271352 supporting_text: ATG2 stably tethers two membranes and transfers lipids between them - description: >- ATG2A forms an ATG2-WIPI/Atg18-family complex at PI3P-rich phagophore edges, linking WIPI phosphoinositide effectors and ATG2A lipid-transfer activity to membrane expansion. molecular_function: id: GO:0043495 label: protein-membrane adaptor activity directly_involved_in: - id: GO:0000045 label: autophagosome assembly locations: - id: GO:0000407 label: phagophore assembly site supported_by: - reference_id: PMID:31271352 supporting_text: we place the ATG2-WIPI complex between the ER and the phagophore edge - reference_id: PMID:32483132 supporting_text: WIPI4 forms a complex with ATG2A/B proposed_new_terms: [] suggested_questions: - question: >- Should human ATG2A be annotated to phosphatidylinositol-3-phosphate binding only as part of a WIPI/Atg18-containing complex, rather than as an independent ATG2A molecular function? experts: - GO autophagy editors - autophagy lipid-transfer experts - question: >- Which selective autophagy cargo pathways have ATG2A-specific evidence beyond the general requirement for ATG2A-mediated phagophore expansion? experts: - GO autophagy editors - Proteostasis Consortium ALP curators - question: >- Should GO:0062079 be updated to explicitly mention mammalian ATG2-WIPI complexes, since the current definition names the Saccharomyces cerevisiae ATG2-ATG18 composition? experts: - GO cellular-component editors - ComplexPortal curators - question: >- Given the ANKFY1 finding that ATG2A can accept lipids from PI3P-positive endosomes, should ATG2A localization/process annotations extend beyond ER-phagophore contact sites to endosome-phagophore interfaces, or is this best captured by an ANKFY1-dependent recruitment annotation rather than a new ATG2A site? experts: - GO autophagy editors - autophagy membrane-contact-site experts - question: >- Does human ATG2A (as opposed to ATG2B) have a direct, LIR/ATG8-dependent role in non-canonical autophagy (CASM) and lysosome repair upon lysosomal damage, distinct from its WIPI4-dependent canonical phagophore-expansion function? experts: - GO autophagy editors - lysosome biology experts suggested_experiments: - experiment_type: Selective-autophagy separation-of-function rescue description: >- Rescue ATG2A/ATG2B double-knockout human cells with ATG2A variants that selectively disrupt WIPI binding, TOM40/MAM targeting, or ATG9A association, then quantify mitophagy, pexophagy, ER-phagy, and glycophagy reporters alongside bulk autophagic flux. hypothesis: >- ATG2A is required for selective-autophagy reporter completion primarily through its general phagophore-expansion function, not through cargo-specific recognition. - experiment_type: Endogenous ATG2-WIPI complex composition assay description: >- Use starvation time courses with endogenous tagging or proximity labeling of ATG2A, WIPI1/2/3/4, and ATG9A, followed by quantitative proteomics and imaging at ER-phagophore contact sites. hypothesis: >- Human ATG2A participates in condition- and stage-specific ATG2-WIPI/Atg18 complexes whose component composition explains the PN-projected ATG2-ATG18 complex annotation.