id: Q6ZNE5 gene_symbol: ATG14 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ATG14/Barkor/ATG14L is the autophagy-specific regulatory and membrane-adaptor subunit of the human class III PI3K complex I (PI3KC3-C1). It targets the PIK3C3/VPS34-PIK3R4/VPS15-BECN1 complex to ER-associated omegasome/phagophore membranes for local PI3P production and autophagosome assembly, and it also promotes later STX17-SNAP29/VAMP8-dependent autophagosome-endolysosome fusion. Its main cellular roles are autophagy initiation and autophagosome maturation rather than class I PI3K/AKT signaling. alternative_products: - name: '1' id: Q6ZNE5-1 - name: '2' id: Q6ZNE5-2 sequence_note: VSP_013931 existing_annotations: - term: id: GO:0035014 label: phosphatidylinositol 3-kinase regulator activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: ATG14 has a core PI3KC3-C1 regulatory role. action: ACCEPT reason: Accept as a core molecular function. ATG14 targets and regulates the Beclin1/VPS34/VPS15 class III PI3K complex at ER/phagophore membranes for autophagosome biogenesis. additional_reference_ids: - GO_REF:0000033 - PMID:18843052 - PMID:19050071 - PMID:19270696 - PMID:20713597 - PMID:21518905 - PMID:22314358 - PMID:25490155 - PMID:40442316 - file:human/ATG14/ATG14-uniprot.txt supported_by: - &id001 reference_id: PMID:20713597 supporting_text: Atg14L recruits a subset of class III PI3-kinase to the ER - &id005 reference_id: PMID:21518905 supporting_text: PI3KC3 recruitment and autophagy stimulation by Barkor/Atg14(L) require the BATS domain - &id004 reference_id: PMID:40442316 supporting_text: PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14 - &id011 reference_id: file:human/ATG14/ATG14-uniprot.txt supporting_text: Required for both basal and inducible autophagy; determines the localization of PI3KC3-C1 - term: id: GO:0043495 label: protein-membrane adaptor activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: ATG14 acts as a protein-membrane adaptor for PI3KC3-C1 and for autophagosome fusion machinery. action: ACCEPT reason: Accept as a core molecular function. ATG14 couples PI3KC3-C1 to ER/omegasome/autophagic membranes through the BATS and ER-targeting regions and also couples mature autophagosomes to STX17-SNAP29/VAMP8 fusion machinery. additional_reference_ids: - GO_REF:0000033 - PMID:20713597 - PMID:21518905 - PMID:25686604 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id001 - &id012 reference_id: PMID:21518905 supporting_text: the BATS domain directly binds to the membrane - &id002 reference_id: PMID:25686604 supporting_text: ATG14 binds to the SNARE core domain of STX17 through its coiled-coil domain - &id003 reference_id: file:human/ATG14/ATG14-uniprot.txt supporting_text: Binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction - term: id: GO:0016240 label: autophagosome membrane docking evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Autophagosome membrane docking is a core ATG14 late-autophagy function. action: ACCEPT reason: Accept as core. ATG14 oligomerization, membrane tethering, and STX17-SNAP29 binding prime autophagosomes for VAMP8-dependent endolysosome fusion. additional_reference_ids: - GO_REF:0000033 - PMID:25686604 - PMID:37632749 - file:human/ATG14/ATG14-uniprot.txt supported_by: - &id009 reference_id: PMID:25686604 supporting_text: ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes - *id002 - &id026 reference_id: PMID:25686604 supporting_text: autophagosomes still efficiently form but their fusion with endolysosomes is blocked - *id003 - term: id: GO:0035032 label: phosphatidylinositol 3-kinase complex, class III evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: The class III PI3K complex assignment is correct but should be narrowed to the ATG14-containing PI3KC3-C1/type I autophagy complex. Cryo-EM of human PI3KC3-C1 (PDB 9MHF/9MHG/9MHH) resolves ATG14 as one of the four heterotetramer subunits alongside VPS34, VPS15, and BECN1. action: MODIFY reason: Modify to the more specific class III PI3K complex type I term. ATG14 is the autophagy-specific PI3KC3-C1 subunit, whereas the parent class III PI3K complex term obscures the C1 versus C2 distinction that matters for the PN autophagy branch. proposed_replacement_terms: - &id015 id: GO:0034271 label: phosphatidylinositol 3-kinase complex, class III, type I additional_reference_ids: - GO_REF:0000033 - PMID:18843052 - PMID:19050071 - PMID:19270696 - PMID:20713597 - PMID:21518905 - PMID:22314358 - PMID:25490155 - PMID:40442316 - PMID:39913640 - file:human/ATG14/ATG14-uniprot.txt supported_by: - &id040 reference_id: PMID:39913640 supporting_text: PI3KC3-C1 is a heterotetrameric complex that comprises one subunit each of the VPS34 lipid kinase, the regulatory scaffold VPS15 (vacuolar protein sorting 15, also known as PIK3R4, phosphoinositide-3-kinase regulatory subunit 4), BECN1 (beclin 1, autophagy related), and the autophagy specific subunit ATG14 - &id041 reference_id: PMID:39913640 supporting_text: still no structures of the autophagy-specific PI3KC3-C1 have been resolved at a high enough resolution to place amino acid side chains. We determined the PI3KC3-C1 structure at a best local resolution of 3.26 Å - &id017 reference_id: PMID:18843052 supporting_text: human Atg14 and UVRAG interact with Beclin 1 and Vps34 - &id019 reference_id: PMID:19050071 supporting_text: direct interaction with Beclin 1 in the human phosphatidylinositol 3-kinase class III complex - &id021 reference_id: PMID:19270696 supporting_text: Atg14L and UVRAG bind to Beclin 1 in a mutually exclusive manner - &id020 reference_id: PMID:25490155 supporting_text: early autophagy consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14 - *id004 - &id016 reference_id: file:human/ATG14/ATG14-uniprot.txt supporting_text: Component of the PI3K complex I in which PIK3C3, PIK3R4 and BECN1 are associated with ATG14 - term: id: GO:0000045 label: autophagosome assembly evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Autophagosome assembly is a core ATG14 process. action: ACCEPT reason: Accept as core. Multiple studies show that ATG14/Barkor is required for LC3 lipidation, omegasome formation, ER-localized PI3P production, and autophagosome formation. additional_reference_ids: - GO_REF:0000033 - PMID:18843052 - PMID:19050071 - PMID:19270696 - PMID:20713597 - PMID:21518905 - PMID:22314358 - PMID:25490155 - PMID:40442316 - PMID:39913640 - file:human/ATG14/ATG14-uniprot.txt supported_by: - &id007 reference_id: PMID:18843052 supporting_text: Silencing of human Atg14 in HeLa cells suppresses autophagosome formation - &id010 reference_id: PMID:19050071 supporting_text: compromises starvation- and rapamycin-induced LC3 lipidation - &id008 reference_id: PMID:19270696 supporting_text: Knockout of Atg14L in mouse ES cells caused a defect in autophagosome formation - *id001 - *id005 - &id006 reference_id: PMID:40442316 supporting_text: All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation - &id042 reference_id: PMID:39913640 supporting_text: PI3KC3-C1 produces phosphatidylinositol (PI) 3-phosphate (PI3P) on the phagophore, which is the precursor to the autophagosome - term: id: GO:0000423 label: mitophagy evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Mitophagy is too cargo-specific for the accessible ATG14 evidence. action: MODIFY reason: Modify to autophagosome assembly. ATG14 is required for canonical autophagosome biogenesis and PI3KC3-C1 activation, but the cached ATG14 papers do not establish a direct ATG14-specific mitophagy function beyond the general requirement of core autophagy machinery. proposed_replacement_terms: - &id031 id: GO:0000045 label: autophagosome assembly additional_reference_ids: - GO_REF:0000033 - PMID:18843052 - PMID:19270696 - PMID:20713597 - PMID:40442316 supported_by: - *id006 - *id007 - *id001 - *id008 - term: id: GO:0005776 label: autophagosome evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Autophagosome localization/activity context is supported. action: ACCEPT reason: Accept as core localization. ATG14 localizes to isolation membranes/autophagosomes during autophagy and to mature autophagosomes during STX17-dependent fusion. additional_reference_ids: - GO_REF:0000033 - PMID:19270696 - PMID:25686604 - file:human/ATG14/ATG14-uniprot.txt supported_by: - &id014 reference_id: PMID:19270696 supporting_text: GFP-Atg14L localized to the isolation membrane and autophagosome, as well as to the ER - *id009 - &id013 reference_id: file:human/ATG14/ATG14-uniprot.txt supporting_text: Cytoplasm; endoplasmic reticulum membrane; preautophagosomal structure membrane; autophagosome membrane - term: id: GO:0009267 label: cellular response to starvation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Starvation response is a supported induction context, but the core process is autophagy/autophagosome assembly. action: KEEP_AS_NON_CORE reason: Keep as non-core. Starvation is a major experimental and physiological trigger for ATG14-dependent autophagy, while the direct ATG14 function is PI3KC3-C1 recruitment/regulation for autophagosome formation. additional_reference_ids: - GO_REF:0000033 - PMID:19050071 - PMID:20713597 - PMID:23878393 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id010 - *id001 - &id028 reference_id: PMID:23878393 supporting_text: phosphorylation at these sites is necessary for maximal autophagy - *id011 - term: id: GO:0097629 label: extrinsic component of omegasome membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: ATG14 is an extrinsic component of omegasome membranes during autophagy initiation. action: ACCEPT reason: Accept as core location/context. ATG14-dependent PI3KC3 recruitment creates PI3P at ER-associated omegasomes, and the BATS domain targets curved PtdIns(3)P-rich autophagic membranes. additional_reference_ids: - GO_REF:0000033 - PMID:20713597 - PMID:21518905 - file:human/ATG14/ATG14-uniprot.txt supported_by: - &id030 reference_id: PMID:20713597 supporting_text: Knockdown of Atg14L leads to the disappearance of the DFCP1-positive omegasome - *id012 - *id013 - term: id: GO:0097632 label: extrinsic component of phagophore assembly site membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: ATG14 is an extrinsic component of the phagophore assembly site membrane. action: ACCEPT reason: Accept as core location/context. ATG14 localizes to early autophagic membranes and recruits PI3KC3 activity needed for phagophore/omegasome PI3P production. additional_reference_ids: - GO_REF:0000033 - PMID:18843052 - PMID:20713597 - PMID:21518905 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id001 - *id005 - &id018 reference_id: PMID:18843052 supporting_text: Atg14 is present on autophagic isolation membranes - *id013 - term: id: GO:0000421 label: autophagosome membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Autophagosome membrane localization is supported. action: ACCEPT reason: Accept as core location. ATG14 localizes to autophagosome membranes and binds autophagic SNARE machinery on mature autophagosomes. additional_reference_ids: - GO_REF:0000044 - PMID:19270696 - PMID:25686604 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id014 - *id009 - *id013 - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Cytoplasmic localization is supported as the broad ATG14 location. action: ACCEPT reason: Accept as a broad location. ATG14 is cytosolic under nutrient-rich conditions and redistributes to autophagic cytoplasmic foci after induction. additional_reference_ids: - GO_REF:0000120 - PMID:19050071 - PMID:37632749 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id010 - *id013 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Endoplasmic reticulum membrane localization is a core ATG14 autophagy-initiation context. action: ACCEPT reason: Accept as core location. ATG14 targets PI3KC3-C1 to the ER/omegasome platform where PI3P is generated for autophagosome formation. additional_reference_ids: - GO_REF:0000044 - PMID:19270696 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id014 - *id001 - *id013 - term: id: GO:0032991 label: protein-containing complex evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: part_of review: summary: Protein-containing complex is true but too generic for ATG14. action: MODIFY reason: Modify to PI3KC3-C1/type I class III PI3K complex. ATG14 is specifically the autophagy-directed regulatory subunit of PI3KC3-C1 rather than merely part of an unspecified protein complex. proposed_replacement_terms: - *id015 additional_reference_ids: - GO_REF:0000117 - PMID:18843052 - PMID:40442316 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id004 - *id016 - *id017 - term: id: GO:0034045 label: phagophore assembly site membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Phagophore assembly site membrane localization is supported. action: ACCEPT reason: Accept as core location/context. ATG14 is detected on isolation/phagophore membranes and helps recruit PI3KC3-C1 to those early autophagic structures. additional_reference_ids: - GO_REF:0000044 - PMID:18843052 - PMID:19050071 - PMID:19270696 - PMID:20713597 - PMID:22314358 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id018 - *id014 - *id001 - &id027 reference_id: PMID:22314358 supporting_text: Atg14L-containing complex is primarily involved in early stage autophagosome formation by promoting autophagosome nucleation and expansion - *id013 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19050071 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:19050071 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id019 - *id010 - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20562859 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:20562859 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21062745 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:21062745 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22081109 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:22081109 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22493499 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:22493499 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23112296 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:23112296 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23332761 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:23332761 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23954414 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:23954414 - file:human/ATG14/ATG14-uniprot.txt supported_by: - reference_id: file:human/ATG14/ATG14-uniprot.txt supporting_text: Interacts with BECN2 via the coiled-coil domain - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24034250 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:24034250 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24785657 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:24785657 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25490155 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:25490155 - file:human/ATG14/ATG14-uniprot.txt - PMID:40442316 supported_by: - *id020 - *id004 - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25594178 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:25594178 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26496610 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:26496610 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:28514442 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:32296183 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33422265 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:33422265 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:33961781 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:34524948 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:34524948 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35271311 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:35271311 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005930 label: axoneme evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Axoneme localization is by similarity and is not the proteostasis-network core function. action: KEEP_AS_NON_CORE reason: Keep as non-core. UniProt records ciliary axoneme localization by similarity, but the human ATG14 evidence reviewed here is dominated by autophagy-specific PI3KC3-C1 and autophagosome-fusion roles. additional_reference_ids: - GO_REF:0000107 - file:human/ATG14/ATG14-uniprot.txt supported_by: - &id034 reference_id: file:human/ATG14/ATG14-uniprot.txt supporting_text: Also localizes to discrete punctae along the ciliary axoneme and to the base of the ciliary axoneme by similarity - term: id: GO:0006914 label: autophagy evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Autophagy is a core ATG14 process. action: ACCEPT reason: Accept as core. ATG14/Barkor is repeatedly shown to be required for basal and inducible autophagy through PI3KC3-C1 recruitment and autophagosome formation. additional_reference_ids: - GO_REF:0000120 - PMID:19050071 - PMID:19270696 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id010 - &id022 reference_id: PMID:19050071 supporting_text: Overexpression of Barkor leads to autophagy activation and increased number and enlarged volume of autophagosomes - *id008 - *id001 - *id011 - term: id: GO:0035032 label: phosphatidylinositol 3-kinase complex, class III evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: part_of review: summary: The class III PI3K complex assignment is correct but should be narrowed to the ATG14-containing PI3KC3-C1/type I autophagy complex. action: MODIFY reason: Modify to the more specific class III PI3K complex type I term. ATG14 is the autophagy-specific PI3KC3-C1 subunit, whereas the parent class III PI3K complex term obscures the C1 versus C2 distinction that matters for the PN autophagy branch. proposed_replacement_terms: - *id015 additional_reference_ids: - GO_REF:0000107 - PMID:18843052 - PMID:19050071 - PMID:19270696 - PMID:20713597 - PMID:21518905 - PMID:22314358 - PMID:25490155 - PMID:40442316 - PMID:39913640 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id040 - *id017 - *id019 - *id021 - *id020 - *id004 - *id016 - term: id: GO:0042149 label: cellular response to glucose starvation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Glucose starvation response is a valid induction context, not the primary ATG14 function. action: KEEP_AS_NON_CORE reason: Keep as non-core. Nutrient/glucose starvation is an autophagy stimulus in ATG14 studies; the core annotatable role is autophagosome assembly and PI3KC3-C1 regulation. additional_reference_ids: - GO_REF:0000107 - PMID:19050071 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id010 - *id001 - *id011 - term: id: GO:0044233 label: mitochondria-associated endoplasmic reticulum membrane contact site evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Mitochondria-associated ER membrane contact-site localization is plausible but secondary. action: KEEP_AS_NON_CORE reason: Keep as non-core. ATG14 is reported in ER/autophagosome contexts and STX17-linked literature places ATG14 near ER-mitochondria contact sites, but this is not the main PN functional annotation. additional_reference_ids: - GO_REF:0000107 - PMID:25686604 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id009 - *id013 - term: id: GO:0045335 label: phagocytic vesicle evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Phagocytic vesicle localization is not directly established for ATG14 in the cached evidence. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. ATG14 participates in antimicrobial/xenophagy contexts, but the reviewed evidence supports autophagic membranes and cytosol/ER/autophagosome locations rather than a direct phagocytic vesicle localization. additional_reference_ids: - GO_REF:0000107 - PMID:19050071 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id010 - *id013 - term: id: GO:0006622 label: protein targeting to lysosome evidence_type: NAS original_reference_id: PMID:16467569 qualifier: involved_in review: summary: Protein targeting to lysosome is too broad for ATG14; the supported trafficking role is endosome/autophagosome-to-lysosome maturation/fusion. action: MODIFY reason: Modify to endosome to lysosome transport. ATG14 supports endosome maturation through Snapin and promotes autophagosome-endolysosome fusion, rather than acting as a general lysosomal protein-targeting factor. proposed_replacement_terms: - &id023 id: GO:0008333 label: endosome to lysosome transport additional_reference_ids: - PMID:16467569 - PMID:22797916 - PMID:25686604 supported_by: - &id024 reference_id: PMID:22797916 supporting_text: Atg14L binds to and colocalizes with the fusogenic SNARE effector protein Snapin to facilitate endosome maturation - &id025 reference_id: PMID:22797916 supporting_text: atg14l knockdown significantly delayed the late stage of endocytic trafficking - *id009 - term: id: GO:0016236 label: macroautophagy evidence_type: NAS original_reference_id: PMID:40442316 qualifier: involved_in review: summary: Macroautophagy is a core ATG14 process. Cryo-EM of human PI3KC3-C1 (PDB 9MHF) places ATG14 as the autophagy-specific subunit of the heterotetramer that produces PI3P on the phagophore during macroautophagy. action: ACCEPT reason: Accept as core. ATG14 is the autophagy-specific PI3KC3-C1 subunit required for macroautophagy initiation and autophagosome formation. additional_reference_ids: - PMID:40442316 - PMID:19050071 - PMID:19270696 - PMID:20713597 - PMID:39913640 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id006 - *id010 - *id008 - *id001 - *id040 - *id011 - term: id: GO:0016241 label: regulation of macroautophagy evidence_type: IDA original_reference_id: PMID:10625637 qualifier: involved_in review: summary: ATG14 positively regulates macroautophagy through PI3KC3-C1. action: ACCEPT reason: Accept as core process regulation. Depletion impairs, and overexpression stimulates, autophagy/autophagosome formation; structurally ATG14 is part of the PI3KC3-C1 initiation complex. additional_reference_ids: - PMID:10625637 - PMID:19050071 - PMID:40442316 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id010 - *id022 - *id006 - *id011 - term: id: GO:0035032 label: phosphatidylinositol 3-kinase complex, class III evidence_type: IPI original_reference_id: PMID:25490155 qualifier: part_of review: summary: The class III PI3K complex assignment is correct but should be narrowed to the ATG14-containing PI3KC3-C1/type I autophagy complex. action: MODIFY reason: Modify to the more specific class III PI3K complex type I term. ATG14 is the autophagy-specific PI3KC3-C1 subunit, whereas the parent class III PI3K complex term obscures the C1 versus C2 distinction that matters for the PN autophagy branch. proposed_replacement_terms: - *id015 additional_reference_ids: - PMID:25490155 - PMID:18843052 - PMID:19050071 - PMID:19270696 - PMID:20713597 - PMID:21518905 - PMID:22314358 - PMID:40442316 - PMID:39913640 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id040 - *id017 - *id019 - *id021 - *id020 - *id004 - *id016 - term: id: GO:0035032 label: phosphatidylinositol 3-kinase complex, class III evidence_type: IPI original_reference_id: PMID:40442316 qualifier: part_of review: summary: The class III PI3K complex assignment is correct but should be narrowed to the ATG14-containing PI3KC3-C1/type I autophagy complex. action: MODIFY reason: Modify to the more specific class III PI3K complex type I term. ATG14 is the autophagy-specific PI3KC3-C1 subunit, whereas the parent class III PI3K complex term obscures the C1 versus C2 distinction that matters for the PN autophagy branch. proposed_replacement_terms: - *id015 additional_reference_ids: - PMID:40442316 - PMID:18843052 - PMID:19050071 - PMID:19270696 - PMID:20713597 - PMID:21518905 - PMID:22314358 - PMID:25490155 - PMID:39913640 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id040 - *id017 - *id019 - *id021 - *id020 - *id004 - *id016 - term: id: GO:0036092 label: phosphatidylinositol-3-phosphate biosynthetic process evidence_type: IDA original_reference_id: PMID:8999962 qualifier: involved_in review: summary: ATG14 supports PI3P biosynthesis as the targeting/regulatory PI3KC3-C1 subunit, not as the catalytic kinase. action: ACCEPT reason: Accept as process contribution. ATG14 recruits PI3KC3-C1 to ER/phagophore membranes and is required for local PI3P production during autophagy initiation; PIK3C3/VPS34 remains the catalytic lipid kinase. additional_reference_ids: - PMID:8999962 - PMID:20713597 - PMID:21518905 - PMID:40442316 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id001 - *id005 - *id004 - *id016 - term: id: GO:0045022 label: early endosome to late endosome transport evidence_type: IDA original_reference_id: PMID:14617358 qualifier: involved_in review: summary: Early-to-late endosome transport is better captured as ATG14-supported endosome-to-lysosome transport/endosome maturation. action: MODIFY reason: Modify to endosome to lysosome transport. The original hVPS34/p150 Rab7 paper does not establish an ATG14-specific early-to-late endosome role, while ATG14-specific Snapin evidence supports endosome maturation and late endocytic trafficking. proposed_replacement_terms: - *id023 additional_reference_ids: - PMID:14617358 - PMID:22797916 supported_by: - *id024 - *id025 - term: id: GO:0097352 label: autophagosome maturation evidence_type: IDA original_reference_id: PMID:10625637 qualifier: involved_in review: summary: Autophagosome maturation is supported by ATG14 fusion/tethering biology. action: ACCEPT reason: Accept as core late-autophagy process. ATG14 binds STX17-SNAP29 on mature autophagosomes and promotes VAMP8-dependent autophagosome-endolysosome fusion. additional_reference_ids: - PMID:10625637 - PMID:25686604 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id009 - *id002 - *id026 - *id003 - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:19050071 qualifier: located_in review: summary: Cytoplasmic localization is supported as the broad ATG14 location. action: ACCEPT reason: Accept as a broad location. ATG14 is cytosolic under nutrient-rich conditions and redistributes to autophagic cytoplasmic foci after induction. additional_reference_ids: - PMID:19050071 - PMID:37632749 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id010 - *id013 - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:37632749 qualifier: located_in review: summary: Cytoplasmic localization is supported as the broad ATG14 location. action: ACCEPT reason: Accept as a broad location. ATG14 is cytosolic under nutrient-rich conditions and redistributes to autophagic cytoplasmic foci after induction. additional_reference_ids: - PMID:37632749 - PMID:19050071 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id010 - *id013 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: EXP original_reference_id: PMID:19270696 qualifier: located_in review: summary: Endoplasmic reticulum membrane localization is a core ATG14 autophagy-initiation context. action: ACCEPT reason: Accept as core location. ATG14 targets PI3KC3-C1 to the ER/omegasome platform where PI3P is generated for autophagosome formation. additional_reference_ids: - PMID:19270696 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id014 - *id001 - *id013 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: EXP original_reference_id: PMID:20713597 qualifier: located_in review: summary: Endoplasmic reticulum membrane localization is a core ATG14 autophagy-initiation context. action: ACCEPT reason: Accept as core location. ATG14 targets PI3KC3-C1 to the ER/omegasome platform where PI3P is generated for autophagosome formation. additional_reference_ids: - PMID:20713597 - PMID:19270696 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id014 - *id001 - *id013 - term: id: GO:0034045 label: phagophore assembly site membrane evidence_type: EXP original_reference_id: PMID:18843052 qualifier: located_in review: summary: Phagophore assembly site membrane localization is supported. action: ACCEPT reason: Accept as core location/context. ATG14 is detected on isolation/phagophore membranes and helps recruit PI3KC3-C1 to those early autophagic structures. additional_reference_ids: - PMID:18843052 - PMID:19050071 - PMID:19270696 - PMID:20713597 - PMID:22314358 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id018 - *id014 - *id001 - *id027 - *id013 - term: id: GO:0034045 label: phagophore assembly site membrane evidence_type: EXP original_reference_id: PMID:19050071 qualifier: located_in review: summary: Phagophore assembly site membrane localization is supported. action: ACCEPT reason: Accept as core location/context. ATG14 is detected on isolation/phagophore membranes and helps recruit PI3KC3-C1 to those early autophagic structures. additional_reference_ids: - PMID:19050071 - PMID:18843052 - PMID:19270696 - PMID:20713597 - PMID:22314358 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id018 - *id014 - *id001 - *id027 - *id013 - term: id: GO:0034045 label: phagophore assembly site membrane evidence_type: EXP original_reference_id: PMID:22314358 qualifier: located_in review: summary: Phagophore assembly site membrane localization is supported. action: ACCEPT reason: Accept as core location/context. ATG14 is detected on isolation/phagophore membranes and helps recruit PI3KC3-C1 to those early autophagic structures. additional_reference_ids: - PMID:22314358 - PMID:18843052 - PMID:19050071 - PMID:19270696 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id018 - *id014 - *id001 - *id027 - *id013 - term: id: GO:0061635 label: regulation of protein complex stability evidence_type: IMP original_reference_id: PMID:23878393 qualifier: involved_in review: summary: Protein-complex stability is not the best description of the ATG14 evidence from this paper. action: MODIFY reason: Modify to positive regulation of protein phosphorylation. The accessible evidence for this reference supports Atg14-dependent Beclin 1 phosphorylation required for maximal autophagy, not a direct protein-complex-stability function. proposed_replacement_terms: - id: GO:0001934 label: positive regulation of protein phosphorylation additional_reference_ids: - PMID:23878393 - file:human/ATG14/ATG14-uniprot.txt supported_by: - &id032 reference_id: PMID:23878393 supporting_text: human Atg14 is critical in controlling an autophagy-dependent phosphorylation of beclin-1 - *id028 - &id033 reference_id: file:human/ATG14/ATG14-uniprot.txt supporting_text: Stimulates phosphorylation of BECN1, but suppresses phosphorylation of PIK3C3 by AMPK - term: id: GO:0043491 label: phosphatidylinositol 3-kinase/protein kinase B signal transduction evidence_type: IDA original_reference_id: PMID:21062745 qualifier: involved_in review: summary: PI3K/AKT signaling is not an appropriate ATG14 process annotation from the Rubicon paper. action: REMOVE reason: Remove. PMID:21062745 supports Rubicon as a negative regulator of hVps34/PI3KC3 and autophagosome maturation; it does not make ATG14 a class I PI3K/AKT signaling component. additional_reference_ids: - PMID:21062745 - file:human/ATG14/ATG14-uniprot.txt supported_by: - &id029 reference_id: PMID:21062745 supporting_text: Rubicon serves as a negative regulator of PI3KC3 and autophagosome maturation - *id011 - term: id: GO:0141039 label: phosphatidylinositol 3-kinase inhibitor activity evidence_type: IDA original_reference_id: PMID:21062745 qualifier: enables review: summary: PI3K inhibitor activity is Rubicon biology, not ATG14 biology. action: REMOVE reason: Remove. The cited Rubicon paper identifies Rubicon as the PI3KC3 lipid-kinase inhibitor, whereas ATG14 is a positive autophagy-specific PI3KC3-C1 targeting/regulatory subunit. additional_reference_ids: - PMID:21062745 - PMID:20713597 - PMID:21518905 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id029 - *id001 - *id005 - *id011 - term: id: GO:0000045 label: autophagosome assembly evidence_type: IDA original_reference_id: PMID:20713597 qualifier: involved_in review: summary: Autophagosome assembly is a core ATG14 process. action: ACCEPT reason: Accept as core. Multiple studies show that ATG14/Barkor is required for LC3 lipidation, omegasome formation, ER-localized PI3P production, and autophagosome formation. additional_reference_ids: - PMID:20713597 - PMID:18843052 - PMID:19050071 - PMID:19270696 - PMID:21518905 - PMID:22314358 - PMID:25490155 - PMID:40442316 - PMID:39913640 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id007 - *id010 - *id008 - *id001 - *id005 - *id006 - *id042 - term: id: GO:0000407 label: phagophore assembly site evidence_type: IDA original_reference_id: PMID:20713597 qualifier: is_active_in review: summary: Phagophore assembly site localization/activity context is supported. action: ACCEPT reason: Accept as core location/context. ATG14 localizes to and organizes the ER/phagophore assembly site where PI3KC3-C1 produces PI3P for autophagosome formation. additional_reference_ids: - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id001 - *id030 - *id013 - term: id: GO:0043495 label: protein-membrane adaptor activity evidence_type: IDA original_reference_id: PMID:20713597 qualifier: enables review: summary: ATG14 acts as a protein-membrane adaptor for PI3KC3-C1 and for autophagosome fusion machinery. action: ACCEPT reason: Accept as a core molecular function. ATG14 couples PI3KC3-C1 to ER/omegasome/autophagic membranes through the BATS and ER-targeting regions and also couples mature autophagosomes to STX17-SNAP29/VAMP8 fusion machinery. additional_reference_ids: - PMID:20713597 - PMID:21518905 - PMID:25686604 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id001 - *id012 - *id002 - *id003 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31806350 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:31806350 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0034045 label: phagophore assembly site membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5682385 qualifier: located_in review: summary: Phagophore assembly site membrane localization is supported. action: ACCEPT reason: Accept as core location/context. ATG14 is detected on isolation/phagophore membranes and helps recruit PI3KC3-C1 to those early autophagic structures. additional_reference_ids: - Reactome:R-HSA-5682385 - PMID:18843052 - PMID:19050071 - PMID:19270696 - PMID:20713597 - PMID:22314358 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id018 - *id014 - *id001 - *id027 - *id013 - term: id: GO:0051020 label: GTPase binding evidence_type: IPI original_reference_id: PMID:25891078 qualifier: enables review: summary: GTPase binding is supported for IRGM interaction but is not the ATG14 core function. action: KEEP_AS_NON_CORE reason: Keep as non-core. ATG14L physically interacts with the human immunity-related GTPase IRGM in antimicrobial autophagy context, but ATG14 core function is PI3KC3-C1 autophagy regulation/adaptor activity. additional_reference_ids: - PMID:25891078 - file:human/ATG14/ATG14-uniprot.txt supported_by: - reference_id: PMID:25891078 supporting_text: IRGM physically interacts with key autophagy regulators, ULK1, Beclin 1, ATG14L and ATG16L1 - *id016 - term: id: GO:0000423 label: mitophagy evidence_type: IMP original_reference_id: PMID:23878393 qualifier: involved_in review: summary: Mitophagy is too cargo-specific for the accessible ATG14 evidence. action: MODIFY reason: Modify to autophagosome assembly. ATG14 is required for canonical autophagosome biogenesis and PI3KC3-C1 activation, but the cached ATG14 papers do not establish a direct ATG14-specific mitophagy function beyond the general requirement of core autophagy machinery. proposed_replacement_terms: - *id031 additional_reference_ids: - PMID:23878393 - PMID:18843052 - PMID:19270696 - PMID:20713597 - PMID:40442316 supported_by: - *id006 - *id007 - *id001 - *id008 - term: id: GO:0098780 label: response to mitochondrial depolarisation evidence_type: IMP original_reference_id: PMID:23878393 qualifier: involved_in review: summary: Response to mitochondrial depolarization is too stimulus-specific for the accessible ATG14 evidence. action: MODIFY reason: Modify to autophagosome assembly. The cited ATG14 evidence supports Beclin 1 phosphorylation and maximal autophagy, but does not directly establish ATG14 as a depolarization-response factor apart from core autophagy machinery requirements. proposed_replacement_terms: - *id031 additional_reference_ids: - PMID:23878393 - PMID:40442316 supported_by: - *id032 - *id028 - *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25686604 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:25686604 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id002 - *id009 - *id003 - term: id: GO:0005776 label: autophagosome evidence_type: IDA original_reference_id: PMID:25686604 qualifier: located_in review: summary: Autophagosome localization/activity context is supported. action: ACCEPT reason: Accept as core localization. ATG14 localizes to isolation membranes/autophagosomes during autophagy and to mature autophagosomes during STX17-dependent fusion. additional_reference_ids: - PMID:25686604 - PMID:19270696 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id014 - *id009 - *id013 - term: id: GO:0016240 label: autophagosome membrane docking evidence_type: IDA original_reference_id: PMID:25686604 qualifier: involved_in review: summary: Autophagosome membrane docking is a core ATG14 late-autophagy function. action: ACCEPT reason: Accept as core. ATG14 oligomerization, membrane tethering, and STX17-SNAP29 binding prime autophagosomes for VAMP8-dependent endolysosome fusion. additional_reference_ids: - PMID:25686604 - PMID:37632749 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id009 - *id002 - *id026 - *id003 - term: id: GO:0009267 label: cellular response to starvation evidence_type: IMP original_reference_id: PMID:23878393 qualifier: involved_in review: summary: Starvation response is a supported induction context, but the core process is autophagy/autophagosome assembly. action: KEEP_AS_NON_CORE reason: Keep as non-core. Starvation is a major experimental and physiological trigger for ATG14-dependent autophagy, while the direct ATG14 function is PI3KC3-C1 recruitment/regulation for autophagosome formation. additional_reference_ids: - PMID:23878393 - PMID:19050071 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id010 - *id001 - *id028 - *id011 - term: id: GO:0010608 label: post-transcriptional regulation of gene expression evidence_type: IMP original_reference_id: PMID:23878393 qualifier: involved_in review: summary: Post-transcriptional regulation of gene expression is unsupported for ATG14 in the reviewed evidence. action: REMOVE reason: Remove. PMID:23878393 concerns ATG14-dependent Beclin 1 phosphorylation and autophagy; it does not support ATG14 as a post-transcriptional gene-expression regulator. additional_reference_ids: - PMID:23878393 supported_by: - *id032 - *id028 - term: id: GO:0016236 label: macroautophagy evidence_type: IMP original_reference_id: PMID:23878393 qualifier: involved_in review: summary: Macroautophagy is a core ATG14 process. action: ACCEPT reason: Accept as core. ATG14 is the autophagy-specific PI3KC3-C1 subunit required for macroautophagy initiation and autophagosome formation. additional_reference_ids: - PMID:23878393 - PMID:19050071 - PMID:19270696 - PMID:20713597 - PMID:40442316 - PMID:39913640 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id006 - *id010 - *id008 - *id001 - *id040 - *id011 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25127057 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:25127057 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id016 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5672012 qualifier: located_in review: summary: Endoplasmic reticulum membrane localization is a core ATG14 autophagy-initiation context. action: ACCEPT reason: Accept as core location. ATG14 targets PI3KC3-C1 to the ER/omegasome platform where PI3P is generated for autophagosome formation. additional_reference_ids: - Reactome:R-HSA-5672012 - PMID:19270696 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id014 - *id001 - *id013 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5679205 qualifier: located_in review: summary: Endoplasmic reticulum membrane localization is a core ATG14 autophagy-initiation context. action: ACCEPT reason: Accept as core location. ATG14 targets PI3KC3-C1 to the ER/omegasome platform where PI3P is generated for autophagosome formation. additional_reference_ids: - Reactome:R-HSA-5679205 - PMID:19270696 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id014 - *id001 - *id013 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5679266 qualifier: located_in review: summary: Endoplasmic reticulum membrane localization is a core ATG14 autophagy-initiation context. action: ACCEPT reason: Accept as core location. ATG14 targets PI3KC3-C1 to the ER/omegasome platform where PI3P is generated for autophagosome formation. additional_reference_ids: - Reactome:R-HSA-5679266 - PMID:19270696 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id014 - *id001 - *id013 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5682385 qualifier: located_in review: summary: Endoplasmic reticulum membrane localization is a core ATG14 autophagy-initiation context. action: ACCEPT reason: Accept as core location. ATG14 targets PI3KC3-C1 to the ER/omegasome platform where PI3P is generated for autophagosome formation. additional_reference_ids: - Reactome:R-HSA-5682385 - PMID:19270696 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id014 - *id001 - *id013 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9755359 qualifier: located_in review: summary: Endoplasmic reticulum membrane localization is a core ATG14 autophagy-initiation context. action: ACCEPT reason: Accept as core location. ATG14 targets PI3KC3-C1 to the ER/omegasome platform where PI3P is generated for autophagosome formation. additional_reference_ids: - Reactome:R-HSA-9755359 - PMID:19270696 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id014 - *id001 - *id013 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9921171 qualifier: located_in review: summary: Endoplasmic reticulum membrane localization is a core ATG14 autophagy-initiation context. action: ACCEPT reason: Accept as core location. ATG14 targets PI3KC3-C1 to the ER/omegasome platform where PI3P is generated for autophagosome formation. additional_reference_ids: - Reactome:R-HSA-9921171 - PMID:19270696 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id014 - *id001 - *id013 - term: id: GO:0001933 label: negative regulation of protein phosphorylation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Negative regulation of protein phosphorylation is supported as a secondary regulatory effect. action: KEEP_AS_NON_CORE reason: Keep as non-core. UniProt records ATG14 suppression of AMPK-dependent PIK3C3 phosphorylation, but the main PN role is PI3KC3-C1 autophagy initiation rather than protein-phosphorylation regulation per se. additional_reference_ids: - GO_REF:0000024 - PMID:23878393 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id033 - *id032 - term: id: GO:0001934 label: positive regulation of protein phosphorylation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Positive regulation of protein phosphorylation is supported as a secondary ATG14 regulatory effect. action: KEEP_AS_NON_CORE reason: Keep as non-core. ATG14 stimulates autophagy-dependent BECN1 phosphorylation required for maximal autophagy, but this is a regulatory mechanism rather than the primary PN function. additional_reference_ids: - GO_REF:0000024 - PMID:23878393 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id032 - *id028 - *id033 - term: id: GO:0035032 label: phosphatidylinositol 3-kinase complex, class III evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: part_of review: summary: The class III PI3K complex assignment is correct but should be narrowed to the ATG14-containing PI3KC3-C1/type I autophagy complex. action: MODIFY reason: Modify to the more specific class III PI3K complex type I term. ATG14 is the autophagy-specific PI3KC3-C1 subunit, whereas the parent class III PI3K complex term obscures the C1 versus C2 distinction that matters for the PN autophagy branch. proposed_replacement_terms: - *id015 additional_reference_ids: - GO_REF:0000024 - PMID:18843052 - PMID:19050071 - PMID:19270696 - PMID:20713597 - PMID:21518905 - PMID:22314358 - PMID:25490155 - PMID:40442316 - PMID:39913640 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id040 - *id017 - *id019 - *id021 - *id020 - *id004 - *id016 - term: id: GO:0042149 label: cellular response to glucose starvation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Glucose starvation response is a valid induction context, not the primary ATG14 function. action: KEEP_AS_NON_CORE reason: Keep as non-core. Nutrient/glucose starvation is an autophagy stimulus in ATG14 studies; the core annotatable role is autophagosome assembly and PI3KC3-C1 regulation. additional_reference_ids: - GO_REF:0000024 - PMID:19050071 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id010 - *id001 - *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1632857 qualifier: located_in review: summary: Cytosol is supported as a broad ATG14 location in nutrient-rich cells and Reactome events. action: ACCEPT reason: Accept as a broad location. ATG14 is cytosolic under nutrient-rich conditions and relocates to autophagic membrane foci after induction. additional_reference_ids: - Reactome:R-HSA-1632857 - PMID:19050071 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id013 - *id010 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5678313 qualifier: located_in review: summary: Cytosol is supported as a broad ATG14 location in nutrient-rich cells and Reactome events. action: ACCEPT reason: Accept as a broad location. ATG14 is cytosolic under nutrient-rich conditions and relocates to autophagic membrane foci after induction. additional_reference_ids: - Reactome:R-HSA-5678313 - PMID:19050071 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id013 - *id010 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5678315 qualifier: located_in review: summary: Cytosol is supported as a broad ATG14 location in nutrient-rich cells and Reactome events. action: ACCEPT reason: Accept as a broad location. ATG14 is cytosolic under nutrient-rich conditions and relocates to autophagic membrane foci after induction. additional_reference_ids: - Reactome:R-HSA-5678315 - PMID:19050071 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id013 - *id010 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5679266 qualifier: located_in review: summary: Cytosol is supported as a broad ATG14 location in nutrient-rich cells and Reactome events. action: ACCEPT reason: Accept as a broad location. ATG14 is cytosolic under nutrient-rich conditions and relocates to autophagic membrane foci after induction. additional_reference_ids: - Reactome:R-HSA-5679266 - PMID:19050071 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id013 - *id010 - term: id: GO:0097629 label: extrinsic component of omegasome membrane evidence_type: IDA original_reference_id: PMID:21518905 qualifier: located_in review: summary: ATG14 is an extrinsic component of omegasome membranes during autophagy initiation. action: ACCEPT reason: Accept as core location/context. ATG14-dependent PI3KC3 recruitment creates PI3P at ER-associated omegasomes, and the BATS domain targets curved PtdIns(3)P-rich autophagic membranes. additional_reference_ids: - PMID:21518905 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id030 - *id012 - *id013 - term: id: GO:0097632 label: extrinsic component of phagophore assembly site membrane evidence_type: IDA original_reference_id: PMID:21518905 qualifier: located_in review: summary: ATG14 is an extrinsic component of the phagophore assembly site membrane. action: ACCEPT reason: Accept as core location/context. ATG14 localizes to early autophagic membranes and recruits PI3KC3 activity needed for phagophore/omegasome PI3P production. additional_reference_ids: - PMID:21518905 - PMID:18843052 - PMID:20713597 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id001 - *id005 - *id018 - *id013 - term: id: GO:0008333 label: endosome to lysosome transport evidence_type: IGI original_reference_id: PMID:22797916 qualifier: acts_upstream_of_or_within review: summary: Endosome-to-lysosome transport is a supported but secondary ATG14 trafficking role. action: KEEP_AS_NON_CORE reason: Keep as non-core. ATG14 has a Snapin-dependent endosome maturation role and a STX17-dependent autophagosome-endolysosome fusion role, but the dominant PN core is autophagy initiation through PI3KC3-C1. additional_reference_ids: - PMID:22797916 - PMID:25686604 supported_by: - *id024 - *id025 - *id009 - term: id: GO:0005930 label: axoneme evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Axoneme localization is by similarity and is not the proteostasis-network core function. action: KEEP_AS_NON_CORE reason: Keep as non-core. UniProt records ciliary axoneme localization by similarity, but the human ATG14 evidence reviewed here is dominated by autophagy-specific PI3KC3-C1 and autophagosome-fusion roles. additional_reference_ids: - GO_REF:0000024 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id034 - term: id: GO:0000045 label: autophagosome assembly evidence_type: IMP original_reference_id: PMID:19270696 qualifier: involved_in review: summary: Autophagosome assembly is a core ATG14 process. action: ACCEPT reason: Accept as core. Multiple studies show that ATG14/Barkor is required for LC3 lipidation, omegasome formation, ER-localized PI3P production, and autophagosome formation. additional_reference_ids: - PMID:19270696 - PMID:18843052 - PMID:19050071 - PMID:20713597 - PMID:21518905 - PMID:22314358 - PMID:25490155 - PMID:40442316 - PMID:39913640 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id007 - *id010 - *id008 - *id001 - *id005 - *id006 - *id042 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19270696 qualifier: enables review: summary: Generic protein binding is not an informative ATG14 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3-C1 membership, protein-membrane adaptor/regulator activity, GTPase binding where appropriate, or STX17-SNAP29/VAMP8 autophagosome-fusion biology rather than generic binding. additional_reference_ids: - PMID:19270696 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id021 - *id008 - *id016 - term: id: GO:0005776 label: autophagosome evidence_type: IDA original_reference_id: PMID:19270696 qualifier: located_in review: summary: Autophagosome localization/activity context is supported. action: ACCEPT reason: Accept as core localization. ATG14 localizes to isolation membranes/autophagosomes during autophagy and to mature autophagosomes during STX17-dependent fusion. additional_reference_ids: - PMID:19270696 - PMID:25686604 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id014 - *id009 - *id013 - term: id: GO:0034045 label: phagophore assembly site membrane evidence_type: IDA original_reference_id: PMID:19270696 qualifier: located_in review: summary: Phagophore assembly site membrane localization is supported. action: ACCEPT reason: Accept as core location/context. ATG14 is detected on isolation/phagophore membranes and helps recruit PI3KC3-C1 to those early autophagic structures. additional_reference_ids: - PMID:19270696 - PMID:18843052 - PMID:19050071 - PMID:20713597 - PMID:22314358 - file:human/ATG14/ATG14-uniprot.txt supported_by: - *id018 - *id014 - *id001 - *id027 - *id013 references: - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10625637 title: Distinct classes of phosphatidylinositol 3'-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. findings: [] - id: PMID:14617358 title: Human VPS34 and p150 are Rab7 interacting partners. findings: [] - id: PMID:16467569 title: Regulation of membrane traffic by phosphoinositide 3-kinases. findings: [] - id: PMID:18843052 title: Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. findings: [] - id: PMID:19050071 title: Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. findings: [] - id: PMID:19270696 title: Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. findings: [] - id: PMID:20562859 title: Network organization of the human autophagy system. findings: [] - id: PMID:20713597 title: Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. findings: [] - id: PMID:21062745 title: The RUN domain of rubicon is important for hVps34 binding, lipid kinase inhibition, and autophagy suppression. findings: [] - id: PMID:21518905 title: Autophagosome targeting and membrane curvature sensing by Barkor/Atg14(L). findings: [] - id: PMID:22081109 title: Inhibition of autophagy by TAB2 and TAB3. findings: [] - id: PMID:22314358 title: Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG. findings: [] - id: PMID:22493499 title: Receptor signaling lymphocyte-activation molecule family 1 (Slamf1) regulates membrane fusion and NADPH oxidase 2 (NOX2) activity by recruiting a Beclin-1/Vps34/ultraviolet radiation resistance-associated gene (UVRAG) complex. findings: [] - id: PMID:22797916 title: Beclin-1-interacting autophagy protein Atg14L targets the SNARE-associated protein Snapin to coordinate endocytic trafficking. findings: [] - id: PMID:23112296 title: Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. findings: [] - id: PMID:23332761 title: Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. findings: [] - id: PMID:23878393 title: Role of membrane association and Atg14-dependent phosphorylation in beclin-1-mediated autophagy. findings: [] - id: PMID:23954414 title: Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. findings: [] - id: PMID:24034250 title: EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. findings: [] - id: PMID:24785657 title: NRBF2 regulates macroautophagy as a component of Vps34 Complex I. findings: [] - id: PMID:25127057 title: TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition. findings: [] - id: PMID:25490155 title: Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex. findings: [] - id: PMID:25594178 title: A kinase-independent role for EGF receptor in autophagy initiation. findings: [] - id: PMID:25686604 title: ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. findings: [] - id: PMID:25891078 title: IRGM governs the core autophagy machinery to conduct antimicrobial defense. findings: [] - id: PMID:26496610 title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances. findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:31806350 title: The ER-Localized Transmembrane Protein TMEM39A/SUSR2 Regulates Autophagy by Controlling the Trafficking of the PtdIns(4)P Phosphatase SAC1. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:33422265 title: ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:34524948 title: Global Proximity Interactome of the Human Macroautophagy Pathway. findings: [] - id: PMID:35271311 title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.' findings: [] - id: PMID:37632749 title: MARCH7-mediated ubiquitination decreases the solubility of ATG14 to inhibit autophagy. findings: [] - id: PMID:40442316 title: Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex. findings: [] - id: PMID:39913640 title: Structural pathway for PI3-kinase regulation by VPS15 in autophagy. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cryo-EM (PDB 9MHF/9MHG/9MHH) of human PI3KC3-C1 resolving ATG14 as the autophagy-specific subunit of the VPS34-VPS15-BECN1-ATG14 heterotetramer; VPS34 is the catalytic lipid kinase while ATG14 is a non-catalytic scaffolding/regulatory subunit. findings: [] - id: PMID:8999962 title: Characterization of p150, an adaptor protein for the human phosphatidylinositol (PtdIns) 3-kinase. Substrate presentation by phosphatidylinositol transfer protein to the p150.Ptdins 3-kinase complex. findings: [] - id: Reactome:R-HSA-1632857 title: ULK1 phosphorylates AMBRA1:BECN1 complex findings: [] - id: Reactome:R-HSA-5672012 title: Beclin-1 complex phosphorylates PtdIns findings: [] - id: Reactome:R-HSA-5678313 title: AMBRA1:DYNLL1,DYNLL2 binds BECN1 complex findings: [] - id: Reactome:R-HSA-5678315 title: BECN1 complex, p-AMBRA1 dissociate from DYNLL1,DYNLL2 findings: [] - id: Reactome:R-HSA-5679205 title: ULK1 phosphorylates Beclin-1 findings: [] - id: Reactome:R-HSA-5679266 title: Beclin-1 complex translocates to the ER findings: [] - id: Reactome:R-HSA-5682385 title: The phagophore extends from the PIP3-enriched structure findings: [] - id: Reactome:R-HSA-9755359 title: SARS-CoV-2 8:class I MHC binds BECN1 findings: [] - id: Reactome:R-HSA-9921171 title: NS1 binds Beclin-1 findings: [] - id: PMID:28218432 title: BECN2 interacts with ATG14 through a metastable coiled-coil to mediate autophagy. findings: [] - id: PMID:39169022 title: Palmitoylation of ULK1 by ZDHHC13 plays a crucial role in autophagy. full_text_unavailable: true findings: - statement: ULK1 phosphorylates ATG14L (at Ser29), and this phosphorylation is required for activation of the class III PI3-kinase (VPS34) and production of phosphatidylinositol 3-phosphate at autophagosome formation sites during autophagy initiation. - id: PMID:40543587 title: The human autophagy-initiating complexes ULK1C and PI3KC3-C1. full_text_unavailable: true findings: - statement: ATG14 is the autophagy-specific regulatory subunit of the class III PI3-kinase complex I (PI3KC3-C1; VPS34-VPS15-BECN1-ATG14), a key initiator of macroautophagy whose assembly and activation it helps coordinate at the molecular level. - id: file:human/ATG14/ATG14-uniprot.txt title: UniProtKB record for ATG14 findings: [] - id: file:human/ATG14/ATG14-notes.md title: ATG14 review notes findings: [] core_functions: - molecular_function: id: GO:0035014 label: phosphatidylinositol 3-kinase regulator activity in_complex: *id015 description: ATG14 is the autophagy-specific PI3KC3-C1 regulatory subunit that recruits and organizes the PIK3C3/VPS34 lipid-kinase complex at ER-associated omegasome/phagophore membranes, enabling local PI3P production for autophagosome assembly and macroautophagy initiation. directly_involved_in: - id: GO:0036092 label: phosphatidylinositol-3-phosphate biosynthetic process - *id031 - id: GO:0016236 label: macroautophagy locations: - id: GO:0005789 label: endoplasmic reticulum membrane - id: GO:0097629 label: extrinsic component of omegasome membrane - &id036 id: GO:0034045 label: phagophore assembly site membrane - &id035 id: GO:0000421 label: autophagosome membrane supported_by: - *id017 - *id010 - *id008 - *id001 - *id005 - *id004 - *id011 - molecular_function: id: GO:0043495 label: protein-membrane adaptor activity description: ATG14 uses membrane-targeting/curvature-sensing and oligomerization regions to bridge autophagy machinery to membranes. This includes BATS-domain targeting of PI3P-rich autophagic membranes and STX17-SNAP29 binding on mature autophagosomes to promote VAMP8-dependent autophagosome-endolysosome fusion. directly_involved_in: - id: GO:0016240 label: autophagosome membrane docking - id: GO:0097352 label: autophagosome maturation - *id023 locations: - id: GO:0005776 label: autophagosome - *id035 - *id036 - id: GO:0005737 label: cytoplasm supported_by: - *id012 - *id009 - *id002 - *id026 - *id024 - *id003 proposed_new_terms: [] suggested_questions: - question: Should all human ATG14 class III PI3K complex annotations be narrowed from the generic parent to PI3KC3-C1/type I complex membership? experts: - GO autophagy editors - ComplexPortal curators - Reactome autophagy curators - question: Should ATG14 mitophagy and mitochondrial-depolarization annotations be retained only with direct cargo-specific evidence, or generalized to autophagosome assembly/macroautophagy? experts: - GO autophagy editors - mitophagy domain experts - ParkinsonsUK-UCL curators - question: Is protein-membrane adaptor activity sufficient for the ATG14 BATS/SNARE roles, or would a more specific autophagosome-fusion adaptor/tether term improve annotation? experts: - GO molecular function editors - autophagosome fusion experts - question: Should ATG14 be annotated as a direct ULK1 phosphorylation substrate (ULK1-mediated Ser29 phosphorylation required for VPS34 activation and PI3P production), e.g. via protein kinase substrate or a regulation-of-PI3K-activity term? experts: - GO autophagy editors - ULK1/PI3KC3 signaling experts suggested_experiments: - description: Use ATG14 knockout cells rescued with coiled-coil, BATS-domain, ER-targeting, and cysteine-oligomerization mutants to measure DFCP1/WIPI recruitment, PI3P production, LC3 lipidation, and autophagic flux. experiment_type: PI3KC3-C1 autophagy-initiation rescue assay hypothesis: ATG14 promotes autophagosome assembly by coupling PI3KC3-C1 to ER/phagophore membranes and enabling local PI3P production. - description: Separate ATG14 initiation and fusion activities using STX17-binding-defective and oligomerization-defective ATG14 mutants, then quantify autophagosome number, autolysosome formation, and cargo degradation. experiment_type: autophagosome maturation separation-of-function assay hypothesis: ATG14 has separable early PI3KC3-C1 recruitment and late STX17-SNAP29/VAMP8 fusion functions. - description: Compare wild-type ATG14 and Snapin-binding-deficient mutants in synchronized endocytic receptor-degradation assays while monitoring autophagic flux in parallel. experiment_type: endocytic trafficking/autophagy separation assay hypothesis: ATG14-dependent endosome maturation is a supported secondary trafficking function that can be separated from its core PI3KC3-C1 autophagy role. - description: Express a non-phosphorylatable ATG14 Ser29Ala mutant (versus wild-type and phosphomimetic) in ATG14-knockout cells and quantify starvation-induced VPS34 lipid-kinase activity, PI3P production, DFCP1/WIPI2 puncta, and LC3 lipidation. experiment_type: ULK1-ATG14 phosphosite separation-of-function assay hypothesis: ULK1-mediated ATG14 Ser29 phosphorylation is required for PI3KC3-C1 activation and local PI3P production at autophagosome formation sites during autophagy initiation.