id: O16466 gene_symbol: atg-18 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:6239 label: Caenorhabditis elegans description: ATG-18 is a PROPPIN (beta-propeller that binds polyphosphoinositides) family protein and WD40 repeat-containing autophagy factor. It functions as a PI3P/PI4P/PI5P/PI(3,5)P2 effector that is recruited to early autophagic membranes (omegasomes/phagophores) via its conserved FRRG motif. ATG-18 plays a distinct role from EPG-6 (WIPI4 ortholog) in autophagosome formation and is required for degradation of protein aggregates, apoptotic cell clearance, xenophagy, and various selective autophagy processes. It acts as a phosphoinositide-binding adapter that promotes phagosome maturation and RAB-5 recruitment during apoptotic cell corpse degradation in phagocytes. existing_annotations: - term: id: GO:0032266 label: phosphatidylinositol-3-phosphate binding evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: IBA annotation based on phylogenetic inference from WIPI family proteins. ATG-18 binds PI3P via its conserved FRRG motif (PMID:21802374, PMID:22451698). action: ACCEPT reason: Core molecular function. Direct experimental evidence in C. elegans shows ATG-18 binds PI3P. "FRRG (amino acids 227-230) in ATG-18 was identified as the PI(3)P binding site, and the mutation from FRRG to FKKG abolished its binding activity in vitro" (PMID:22451698). Also supported by IDA annotation (PMID:21802374). supported_by: - reference_id: PMID:21802374 supporting_text: ATG-18, plays a distinct role in autophagosome formation - reference_id: PMID:22451698 supporting_text: FRRG (amino acids 227-230) in ATG-18 was identified as the PI(3)P binding site - reference_id: file:worm/atg-18/atg-18-deep-research-falcon.md supporting_text: 'model: Edison Scientific Literature' - term: id: GO:0034045 label: phagophore assembly site membrane evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: IBA annotation indicating localization to early autophagic structures. Consistent with WIPI family function at omegasomes/phagophores. action: MARK_AS_OVER_ANNOTATED reason: Core localization. ATG-18 is recruited to PI3P-enriched early autophagic membranes. The Lu et al. 2011 study shows ATG-18 functions at early autophagic structures. "EPG-6 and ATG-18 regulate progression of omegasomes to autophagosomes" (PMID:21802374). [2026-08 re-review against GO issue #29437] Held on a defective term with no correct destination in the current ontology, so recorded as an over-annotation with the needed term proposed rather than left as ACCEPT. GO:0034045 asserts via bounding_layer_of that a membrane bounds the phagophore assembly site, which is a protein condensate with no bounding bilayer (PMID:32025038). The cited evidence places ATG-18 on PI3P-enriched omegasome and phagophore membranes, which is the phagophore membrane proposed under proposed_new_terms. propagation_review: root_cause: TERM_SCOPING_PROBLEM failure_modes: - GRANULARITY_MISMATCH source_entities: - source_id: PANTHER:PTN000132136 source_label: Atg18/WIPI PROPPIN ancestral node source_status: SUPPORTS_TRANSFER comment: >- The node places the PROPPINs correctly on PI3P-rich early autophagic membranes; the defect is that the propagated term names a membrane bounding the assembly site, which does not exist. - source_id: UniProtKB:Q9Y4P8 source_label: WIPI2 (human) source_status: SOURCE_WEAK_OR_INFERRED comment: >- Seed carries the same defective term, so the propagation adds no independent evidence for a PAS membrane. supported_by: - reference_id: PMID:21802374 supporting_text: epg-6 and atg-2 regulate progression of omegasomes to autophagosomes... Another WD40 repeat PtdIns(3)P effector, ATG-18, plays a distinct role in autophagosome formation - term: id: GO:0000422 label: autophagy of mitochondrion evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: IBA annotation inferring mitophagy function. Direct evidence in C. elegans from PMID:30133321 shows ATG-18 is involved in autophagy-mediated mitochondrial consumption during starvation. action: ACCEPT reason: Supported by direct C. elegans evidence. UniProt states "Plays a role in mitophagy, which is the autophagic consumption of mitochondria, in response to dietary restriction" (PMID:30133321). Phylogenetically conserved function. supported_by: - reference_id: PMID:30133321 supporting_text: Nonselective autophagy reduces mitochondrial content during starvation in Caenorhabditis elegans - term: id: GO:0000425 label: pexophagy evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: IBA annotation based on yeast Atg18 function in pexophagy. No direct C. elegans experimental evidence available. action: KEEP_AS_NON_CORE reason: Phylogenetically inferred but not directly demonstrated in C. elegans. The conserved WIPI/ATG18 family function suggests this is plausible, but pexophagy is not a major studied phenotype for C. elegans atg-18. - term: id: GO:0030674 label: protein-macromolecule adaptor activity evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: IBA annotation reflecting the adaptor function of WIPI proteins that bridge PI3P-containing membranes to downstream autophagy machinery. action: ACCEPT reason: Core molecular function. ATG-18/WIPI proteins serve as PI3P effectors that recruit downstream factors. The PROPPIN family architecture with PI-binding sites and effector-binding surfaces supports this adaptor function. ATG-18 is recruited to phagosomes via PI3P and promotes RAB-5 recruitment (PMID:22451698). supported_by: - reference_id: PMID:22451698 supporting_text: EPG-5 and ATG-18 are required for RAB-5 recruitment - term: id: GO:0044804 label: nucleophagy evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: IBA annotation based on yeast Atg18 function. No direct C. elegans experimental evidence for nucleophagy. action: KEEP_AS_NON_CORE reason: Phylogenetically inferred but not directly demonstrated in C. elegans. Nucleophagy is not a well-characterized process in nematodes. - term: id: GO:0061723 label: glycophagy evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: IBA annotation based on Drosophila evidence. No direct C. elegans experimental evidence for glycophagy. action: KEEP_AS_NON_CORE reason: Phylogenetically inferred but not directly demonstrated in C. elegans. While glycogen metabolism occurs in worms, glycophagy involvement of atg-18 is not directly shown. - term: id: GO:0034497 label: protein localization to phagophore assembly site evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: IBA annotation reflecting role in recruiting proteins to nascent autophagosomes. Consistent with WIPI family function. action: ACCEPT reason: Core biological process. ATG-18 as a PI3P effector facilitates recruitment of other autophagy factors to phagophores. The hierarchical analysis in PMID:21802374 positions ATG-18 upstream in autophagosome formation pathway. supported_by: - reference_id: PMID:21802374 supporting_text: We also established the hierarchical relationship of autophagy genes in degradation of protein aggregates - term: id: GO:0080025 label: phosphatidylinositol-3,5-bisphosphate binding evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: IBA annotation consistent with known PROPPIN binding to PI(3,5)P2. Also supported by IDA evidence (PMID:21802374). action: ACCEPT reason: Core molecular function. UniProt and IDA evidence confirm weaker binding to PI(3,5)P2 in addition to stronger PI3P binding. "binds... more weakly to phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2)" (UniProt). supported_by: - reference_id: PMID:21802374 supporting_text: elegans, epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity - term: id: GO:0005829 label: cytosol evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: IBA annotation for cytosolic localization. ATG-18 is cytosolic when not recruited to membranes. action: ACCEPT reason: Consistent with peripheral membrane protein behavior. ATG-18 is in the cytosol prior to recruitment to PI3P-containing membranes during autophagy induction or phagosome formation. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 review: summary: IEA annotation from UniProt subcellular location. Broader than cytosol annotation but accurate. action: ACCEPT reason: General localization is correct. Supported by IDA evidence (PMID:25124690) showing cytoplasmic localization. - term: id: GO:0006914 label: autophagy evidence_type: IEA original_reference_id: GO_REF:0000043 review: summary: IEA annotation from UniProt keyword mapping. Core function of ATG-18 is in autophagy. action: ACCEPT reason: Core biological process. Extensively validated by experimental evidence (PMID:12958363, PMID:21802374, PMID:22451698). ATG-18 is a canonical autophagy gene. supported_by: - reference_id: PMID:12958363 supporting_text: autophagy is a cellular pathway essential for dauer development and life-span extension in C. elegans - term: id: GO:0008289 label: lipid binding evidence_type: IEA original_reference_id: GO_REF:0000043 review: summary: IEA annotation from UniProt keyword. Accurate but less specific than the phosphoinositide binding annotations. action: MARK_AS_OVER_ANNOTATED reason: While technically correct, this is too general. The specific phosphoinositide binding annotations (GO:0032266, GO:0080025, GO:0070273, GO:0010314) are more informative. This adds little beyond those. - term: id: GO:0030670 label: phagocytic vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000044 review: summary: IEA annotation from UniProt subcellular location. ATG-18 is recruited to phagosomal membranes during apoptotic cell degradation. action: ACCEPT reason: Validated by experimental data. PMID:22451698 shows GFP::ATG-18 is recruited to the outer surface of phagosomes containing apoptotic cells in a PI3P-dependent manner. supported_by: - reference_id: PMID:22451698 supporting_text: Both GFP::ATG-18 and EPG-5::GFP appeared on the outer surface of apoptotic Q cells even more prominently than LGG-1::GFP - term: id: GO:0031410 label: cytoplasmic vesicle evidence_type: IEA original_reference_id: GO_REF:0000043 review: summary: IEA annotation from UniProt keyword. General vesicle localization. action: ACCEPT reason: Accurate general localization. ATG-18 localizes to autophagosomes and phagosomes, which are cytoplasmic vesicles. - term: id: GO:0097237 label: cellular response to toxic substance evidence_type: IMP original_reference_id: PMID:27875098 review: summary: IMP annotation showing atg-18 is required for defense against bacterial pore-forming toxin Cry5B. atg-18(gk378) mutants show hypersensitivity to Cry5B toxicity (PMID:27875098). action: ACCEPT reason: Well-supported experimental evidence. "atg-18(gk378)... showed a significant Hpo (Hypersensitive to POre-forming toxin) phenotype to Cry5B killing compare with N2 animals" (PMID:27875098). This represents the xenophagy function of ATG-18. supported_by: - reference_id: PMID:27875098 supporting_text: These atg gene mutants, bec-1(ok691), bec-1(ok700), atg-4.1(tm4364);atg-4.2(tm3949), and atg-18(gk378)... showed a significant Hpo (Hypersensitive to POre-forming toxin) phenotype to Cry5B killing compare with N2 animals - term: id: GO:0001778 label: plasma membrane repair evidence_type: IMP original_reference_id: PMID:27875098 review: summary: IMP annotation showing atg-18 contributes to membrane pore repair after Cry5B toxin exposure. RNAi of atg-18 abolishes intrinsic membrane-pore repair activity (PMID:27875098). action: ACCEPT reason: Experimental evidence supports this annotation. "RNAi depletion of Cry5B-induced atg genes significantly abolished the pore-repair ratio" (PMID:27875098). This is a specialized function related to xenophagy/toxin defense. supported_by: - reference_id: PMID:27875098 supporting_text: autophagy also contributes to the intrinsic membrane pore-repair to defend against Cry5B PFT intoxication - term: id: GO:0098792 label: xenophagy evidence_type: IMP original_reference_id: PMID:27875098 review: summary: IMP annotation showing ATG-18 is required for xenophagic degradation of bacterial pore-forming toxin. Cry5B is internalized and degraded via autophagy in intestinal cells (PMID:27875098). action: ACCEPT reason: Strong experimental support. "autophagy controls the susceptibility of animals to PFT toxicity through xenophagic degradation of PFT and repair of membrane-pore cell-autonomously" (PMID:27875098). supported_by: - reference_id: PMID:27875098 supporting_text: autophagy controls the susceptibility of animals to PFT toxicity through xenophagic degradation of PFT and repair of membrane-pore cell-autonomously in the PFT-targeted intestinal cells - term: id: GO:0036093 label: germ cell proliferation evidence_type: IMP original_reference_id: PMID:28285998 review: summary: IMP annotation showing atg-18 is required for late larval expansion of germline stem cell progenitors (PMID:28285998). action: KEEP_AS_NON_CORE reason: Experimental evidence supports this phenotype, but this is a developmental/pleiotropic effect rather than the core molecular function of ATG-18. "atg-18/WIPI1/2... are required for the late larval expansion of germline stem cell progenitors" (PMID:28285998). supported_by: - reference_id: PMID:28285998 supporting_text: autophagy genes such as bec-1/BECN1/Beclin1, atg-16.2/ATG16L, atg-18/WIPI1/2, and atg-7/ATG7 are required for the late larval expansion of germline stem cell progenitors in the C. elegans gonad - term: id: GO:0042078 label: germ-line stem cell division evidence_type: IMP original_reference_id: PMID:28285998 review: summary: IMP annotation showing atg-18 promotes cell-cycle progression in germline stem cells (PMID:28285998). action: KEEP_AS_NON_CORE reason: Experimental evidence supports this but it represents a downstream developmental effect of autophagy function, not the core molecular role of ATG-18. "ATG-18/WIPI1/2... promote cell-cycle progression" (PMID:28285998). supported_by: - reference_id: PMID:28285998 supporting_text: Similar to DAF-2/IIR, BEC-1/BECN1/Beclin1, ATG-18/WIPI1/2, and ATG-16.2/ATG16L all promote cell-cycle progression - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:25124690 review: summary: IDA annotation based on direct localization studies showing ATG-18 in the cytoplasm (PMID:25124690). action: ACCEPT reason: Direct experimental evidence. "loss of MTM-3 causes increased autophagic association of ATG-18 in a PtdIns3P-dependent manner" implying ATG-18 cycles between cytoplasm and autophagic membranes (PMID:25124690). supported_by: - reference_id: PMID:25124690 supporting_text: loss of MTM-3 causes increased autophagic association of ATG-18 in a PtdIns3P-dependent manner - term: id: GO:0010508 label: positive regulation of autophagy evidence_type: IMP original_reference_id: PMID:25124690 review: summary: IMP annotation showing ATG-18 promotes autophagy. ATG-18 functions downstream of PI3K and is required for autophagosome formation. action: ACCEPT reason: Core function. ATG-18 is a positive regulator of autophagy as a PI3P effector. The study shows ATG-18 association with autophagic structures and its role in autophagosome maturation (PMID:25124690). supported_by: - reference_id: PMID:25124690 supporting_text: MTM-3 acts downstream of the ATG-2/EPG-6 complex... to promote autophagosome maturation into autolysosomes - term: id: GO:0045335 label: phagocytic vesicle evidence_type: IDA original_reference_id: PMID:22451698 review: summary: IDA annotation showing ATG-18 localizes to phagocytic vesicles containing apoptotic cells (PMID:22451698). action: ACCEPT reason: Direct imaging evidence. "GFP::ATG-18... appeared on the outer surface of apoptotic Q cells... 39% for ring... 39% for puncta" (PMID:22451698). ATG-18 is recruited to phagosomes in a PI3P-dependent manner. supported_by: - reference_id: PMID:22451698 supporting_text: Both GFP::ATG-18 and EPG-5::GFP appeared on the outer surface of apoptotic Q cells even more prominently than LGG-1::GFP - term: id: GO:0009792 label: embryo development ending in birth or egg hatching evidence_type: IGI original_reference_id: PMID:21502138 review: summary: IGI annotation indicating genetic interaction with ced genes during embryonic development. Autophagy and apoptosis show redundant roles in embryogenesis. action: KEEP_AS_NON_CORE reason: Developmental phenotype showing genetic interaction. Not a core molecular function of ATG-18 but reflects its role in autophagy which has developmental consequences. supported_by: - reference_id: PMID:21502138 supporting_text: Shared developmental roles and transcriptional control of autophagy and apoptosis in Caenorhabditis elegans. - term: id: GO:0008340 label: determination of adult lifespan evidence_type: IGI original_reference_id: PMID:21906946 review: summary: IGI annotation showing atg-18 genetic interaction in lifespan regulation. Autophagy contributes to longevity in C. elegans. action: KEEP_AS_NON_CORE reason: Pleiotropic developmental/aging phenotype. The primary literature (PMID:12958363, PMID:28557996) supports a role in lifespan extension, but this is a downstream consequence of autophagy function, not a core molecular role. supported_by: - reference_id: PMID:21906946 supporting_text: 2011 Sep 8. Autophagy and lipid metabolism coordinately modulate life span in germline-less C. - term: id: GO:0010314 label: phosphatidylinositol-5-phosphate binding evidence_type: IDA original_reference_id: PMID:21802374 review: summary: IDA annotation showing direct binding to PI5P. UniProt confirms "binds with high affinity to phosphatidylinositols including... phosphatidylinositol 5-phosphate (PtdIns(5)P)" (PMID:21802374). action: ACCEPT reason: Core molecular function demonstrated by direct binding assays. The FRRG motif mediates binding to multiple phosphoinositides including PI5P. supported_by: - reference_id: PMID:21802374 supporting_text: elegans, epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity - term: id: GO:0032266 label: phosphatidylinositol-3-phosphate binding evidence_type: IDA original_reference_id: PMID:21802374 review: summary: IDA annotation demonstrating direct PI3P binding via the FRRG motif. Primary molecular function of ATG-18 for membrane recruitment. action: ACCEPT reason: Core molecular function. Duplicates the IBA annotation but with direct experimental evidence. "FRRG (amino acids 227-230) in ATG-18 was identified as the PI(3)P binding site" and mutation abolishes binding (PMID:21802374, PMID:22451698). supported_by: - reference_id: PMID:22451698 supporting_text: FRRG (amino acids 227-230) in ATG-18 was identified as the PI(3)P binding site, and the mutation from FRRG to FKKG abolished its binding activity in vitro - reference_id: PMID:21802374 supporting_text: 2011 Jul 28. The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes. - term: id: GO:0070273 label: phosphatidylinositol-4-phosphate binding evidence_type: IDA original_reference_id: PMID:21802374 review: summary: IDA annotation showing ATG-18 binds PI4P. UniProt confirms binding to "phosphatidylinositol 4-phosphate (PtdIns(4)P)" (PMID:21802374). action: ACCEPT reason: Core molecular function demonstrated by direct binding assays. The broad phosphoinositide specificity is characteristic of PROPPIN proteins. supported_by: - reference_id: PMID:21802374 supporting_text: epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity - term: id: GO:0080025 label: phosphatidylinositol-3,5-bisphosphate binding evidence_type: IDA original_reference_id: PMID:21802374 review: summary: IDA annotation demonstrating PI(3,5)P2 binding. ATG-18 binds "more weakly to phosphatidylinositol 3,5-bisphosphate" compared to PI3P. action: ACCEPT reason: Core molecular function. Weaker binding than to PI3P but demonstrated experimentally. Duplicates IBA annotation with direct evidence. supported_by: - reference_id: PMID:21802374 supporting_text: epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity - term: id: GO:0043277 label: apoptotic cell clearance evidence_type: IMP original_reference_id: PMID:21183797 review: summary: IMP annotation showing atg-18 is required for clearance of apoptotic cells. RNAi against atg-18 results in lack of cell corpse clearance (PMID:21183797). action: ACCEPT reason: Important functional role. "RNAi against atg-18 or unc-51 also results in a lack of cell corpse clearance" (PMID:21183797). This reflects ATG-18's role in phagosome maturation via PI3P binding. supported_by: - reference_id: PMID:21183797 supporting_text: autophagy genes may also be required for cell corpse clearance, as we find that RNAi against atg-18 or unc-51 also results in a lack of cell corpse clearance - term: id: GO:0048598 label: embryonic morphogenesis evidence_type: IGI original_reference_id: PMID:21285529 review: summary: IGI annotation indicating genetic interaction with ced genes during embryonic morphogenesis. action: KEEP_AS_NON_CORE reason: Developmental phenotype reflecting pleiotropic effects of autophagy deficiency. Not a core molecular function. supported_by: - reference_id: PMID:21285529 supporting_text: Autophagy and apoptosis are redundantly required for C. - term: id: GO:0012501 label: programmed cell death evidence_type: IGI original_reference_id: PMID:17901876 review: summary: IGI annotation showing genetic interaction with cell death genes. Autophagy is required for necrotic cell death. action: KEEP_AS_NON_CORE reason: Genetic interaction phenotype. ATG-18 functions in autophagy which contributes to certain cell death processes, but programmed cell death is not the core function of ATG-18. supported_by: - reference_id: PMID:17901876 supporting_text: 2007 Sep 28. Autophagy is required for necrotic cell death in Caenorhabditis elegans. - term: id: GO:0030163 label: protein catabolic process evidence_type: IMP original_reference_id: PMID:17172799 review: summary: IMP annotation showing autophagy genes including atg-18 promote clearance of polyglutamine protein aggregates (PMID:17172799). action: ACCEPT reason: Core autophagy function. "genetic inactivation of autophagy genes accelerates the accumulation of polyQ40 aggregates" (PMID:17172799). Protein degradation via autophagy is a primary function. supported_by: - reference_id: PMID:17172799 supporting_text: genetic inactivation of autophagy genes accelerates the accumulation of polyQ40 aggregates in C. elegans muscle cells and exacerbates polyQ40-induced muscle dysfunction - term: id: GO:0006914 label: autophagy evidence_type: IGI original_reference_id: PMID:12958363 review: summary: IGI annotation showing atg-18 functions with other autophagy genes including daf-2 in autophagy during dauer formation (PMID:12958363). action: ACCEPT reason: Core function. The seminal Melendez et al. 2003 study established autophagy genes including the AUT10 ortholog (atg-18) as essential for dauer development. "Dauer formation is associated with increased autophagy and also requires C. elegans orthologs of the yeast autophagy genes APG1, APG7, APG8, and AUT10" (PMID:12958363). supported_by: - reference_id: PMID:12958363 supporting_text: Dauer formation is associated with increased autophagy and also requires C. elegans orthologs of the yeast autophagy genes APG1, APG7, APG8, and AUT10 - term: id: GO:0040024 label: dauer larval development evidence_type: IGI original_reference_id: PMID:12958363 review: summary: IGI annotation showing atg-18 is required for proper dauer formation in daf-2 mutants (PMID:12958363). action: ACCEPT reason: Important developmental phenotype demonstrating autophagy requirement. "RNAi-mediated knockdown causes abnormalities in constitutive dauer formation in daf-2 e1370 mutant including a lack of autophagosome formation" (UniProt, PMID:12958363). supported_by: - reference_id: PMID:12958363 supporting_text: autophagy is a cellular pathway essential for dauer development and life-span extension in C. elegans references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: - statement: Phylogenetic analysis (IBA) provides solid support for conserved WIPI family functions - id: GO_REF:0000043 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:12958363 title: Autophagy genes are essential for dauer development and life-span extension in C. elegans. findings: - statement: Established C. elegans autophagy pathway including AUT10/atg-18 ortholog supporting_text: Autophagy genes are essential for dauer development and life-span extension in C. elegans. - statement: Autophagy essential for dauer morphogenesis and lifespan extension supporting_text: Autophagy genes are essential for dauer development and life-span extension in C. elegans. - id: PMID:17172799 title: Autophagy genes protect against disease caused by polyglutamine expansion proteins in Caenorhabditis elegans. findings: - statement: Autophagy genes including atg-18 promote clearance of polyQ aggregates supporting_text: Autophagy genes protect against disease caused by polyglutamine expansion proteins in Caenorhabditis elegans. - statement: Inactivation accelerates aggregate accumulation and exacerbates dysfunction supporting_text: Autophagy genes protect against disease caused by polyglutamine expansion proteins in Caenorhabditis elegans. - id: PMID:17901876 title: Autophagy is required for necrotic cell death in Caenorhabditis elegans. findings: - statement: Genetic interaction between autophagy and cell death pathways supporting_text: Autophagy is required for necrotic cell death in Caenorhabditis elegans. - id: PMID:21183797 title: The Atg6/Vps30/Beclin 1 ortholog BEC-1 mediates endocytic retrograde transport in addition to autophagy in C. elegans. findings: - statement: RNAi against atg-18 results in defective cell corpse clearance supporting_text: The Atg6/Vps30/Beclin 1 ortholog BEC-1 mediates endocytic retrograde transport in addition to autophagy in C. elegans. - statement: Links autophagy to phagosome maturation supporting_text: The Atg6/Vps30/Beclin 1 ortholog BEC-1 mediates endocytic retrograde transport in addition to autophagy in C. elegans. - id: PMID:21285529 title: Autophagy and apoptosis are redundantly required for C. elegans embryogenesis. findings: - statement: Genetic redundancy between autophagy and apoptosis in development supporting_text: Autophagy and apoptosis are redundantly required for C. elegans embryogenesis. - id: PMID:21502138 title: Shared developmental roles and transcriptional control of autophagy and apoptosis in Caenorhabditis elegans. findings: - statement: Developmental roles of autophagy genes including atg-18 supporting_text: Shared developmental roles and transcriptional control of autophagy and apoptosis in Caenorhabditis elegans. - id: PMID:21802374 title: The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes. findings: - statement: ATG-18 plays distinct role from EPG-6 in autophagosome formation supporting_text: The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes. - statement: Both are PI3P-binding WD40 proteins supporting_text: The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes. - statement: Established hierarchical relationships of autophagy genes supporting_text: The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes. - statement: FRRG motif required for PI binding supporting_text: The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes. - id: PMID:21906946 title: Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans. findings: - statement: Autophagy genes contribute to lifespan regulation supporting_text: Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans. - id: PMID:22451698 title: Autophagy genes function sequentially to promote apoptotic cell corpse degradation in the engulfing cell. findings: - statement: ATG-18 recruited to phagosome outer surface supporting_text: Autophagy genes function sequentially to promote apoptotic cell corpse degradation in the engulfing cell. - statement: PI3P binding via FRRG motif required for recruitment and function supporting_text: Autophagy genes function sequentially to promote apoptotic cell corpse degradation in the engulfing cell. - statement: ATG-18 promotes RAB-5 recruitment and phagosome maturation supporting_text: Autophagy genes function sequentially to promote apoptotic cell corpse degradation in the engulfing cell. - statement: Functions in phagocyte for cell corpse degradation supporting_text: Autophagy genes function sequentially to promote apoptotic cell corpse degradation in the engulfing cell. - id: PMID:25124690 title: PI3P phosphatase activity is required for autophagosome maturation and autolysosome formation. findings: - statement: ATG-18 association with autophagosomes depends on PI3P levels supporting_text: PI3P phosphatase activity is required for autophagosome maturation and autolysosome formation. - statement: MTM-3 loss increases ATG-18 autophagic association supporting_text: PI3P phosphatase activity is required for autophagosome maturation and autolysosome formation. - id: PMID:27875098 title: HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans. findings: - statement: atg-18(gk378) hypersensitive to Cry5B pore-forming toxin supporting_text: HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans. - statement: atg-18 required for xenophagic degradation of toxin supporting_text: HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans. - statement: atg-18 required for membrane pore repair supporting_text: HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans. - statement: atg-18 transcriptionally upregulated by Cry5B exposure supporting_text: HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans. - id: PMID:28285998 title: A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development. findings: - statement: atg-18/WIPI1/2 required for germline stem cell proliferation supporting_text: A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development. - statement: Promotes cell-cycle progression via DAF-16/FOXO supporting_text: A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development. - statement: Functions in DAF-2/insulin signaling pathway supporting_text: A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development. - id: PMID:28557996 title: The cell non-autonomous function of ATG-18 is essential for neuroendocrine regulation of Caenorhabditis elegans lifespan. findings: - statement: ATG-18 expressed in neurons and intestinal cells supporting_text: The cell non-autonomous function of ATG-18 is essential for neuroendocrine regulation of Caenorhabditis elegans lifespan. - statement: Regulates neurotransmitter/neuropeptide release supporting_text: The cell non-autonomous function of ATG-18 is essential for neuroendocrine regulation of Caenorhabditis elegans lifespan. - statement: Controls lifespan in response to dietary restriction supporting_text: The cell non-autonomous function of ATG-18 is essential for neuroendocrine regulation of Caenorhabditis elegans lifespan. - id: PMID:30133321 title: Nonselective autophagy reduces mitochondrial content during starvation in Caenorhabditis elegans. findings: - statement: ATG-18 involved in mitophagy during dietary restriction supporting_text: Nonselective autophagy reduces mitochondrial content during starvation in Caenorhabditis elegans. - id: file:worm/atg-18/atg-18-deep-research-falcon.md title: Deep research report on atg-18 findings: [] core_functions: - molecular_function: id: GO:0032266 label: phosphatidylinositol-3-phosphate binding description: ATG-18 is a PROPPIN family phosphoinositide effector that binds PI3P (and other phosphoinositides including PI4P, PI5P, and PI(3,5)P2) via its conserved FRRG motif (amino acids 227-230). This PI3P binding is essential for recruitment to early autophagic membranes (phagophores/omegasomes) and phagosomes, and is absolutely required for its function in autophagy and cell corpse clearance. The RR->KK mutation abolishes binding and function (PMID:21802374, PMID:22451698). - molecular_function: id: GO:0030674 label: protein-macromolecule adaptor activity description: ATG-18 functions as an adaptor/effector that bridges PI3P-containing membranes to downstream autophagy machinery. Its WD40 repeat beta-propeller structure provides binding surfaces for both phosphoinositides and protein partners. In phagocytosis, ATG-18 is co-recruited with RAB-5 and is required for efficient RAB-5/RAB-7 recruitment and phagosome maturation (PMID:22451698). proposed_new_terms: - proposed_name: phagophore membrane proposed_definition: >- The membrane system of a phagophore, comprising its two closely apposed lipid bilayers and the continuous rim that joins them, which expands by lipid acquisition and closes to form the double membrane of an autophagosome. justification: >- GO has autophagosome membrane (GO:0000421) and omegasome membrane (GO:1903349) but no term for the membrane of the phagophore itself, so annotations describing the phagophore membrane have gone to GO:0034045 phagophore assembly site membrane for want of anything better. That term asserts via bounding_layer_of that a membrane bounds the phagophore assembly site, which is a protein condensate with no bounding bilayer (PMID:32025038), and it carries "phagophore" and "isolation membrane" as related synonyms, competing directly with GO:0061908. See GO issue #29437 (recommendation R3). Note the sheet-versus-system question is unresolved upstream - this proposal takes the collective reading; the alternative is "either of the two closely apposed lipid bilayers that form a phagophore". proposed_parent: id: GO:0016020 label: membrane suggested_questions: - question: What are the specific protein partners that ATG-18 recruits or interacts with at the phagophore assembly site in C. elegans, beyond the known ATG-2 interaction? Human WIPI2 recruits ATG16L1 to phagophores. The C. elegans ATG-18 interaction partners for recruiting the ATG12-ATG5-ATG16 conjugation complex are not fully characterized. - question: Does ATG-18 have distinct functions from EPG-6 (WIPI4 ortholog) beyond their different roles in autophagosome biogenesis? Lu et al. 2011 established that ATG-18 and EPG-6 have distinct roles, but the molecular basis for this specificity is not fully understood. suggested_experiments: - description: Systematic identification of ATG-18 interacting proteins using co-immunoprecipitation or proximity labeling approaches to identify effector binding partners. While PI binding is well characterized, the protein interaction network of C. elegans ATG-18 is incomplete compared to mammalian WIPI proteins. - description: Live imaging of ATG-18 dynamics at nascent autophagosomes to determine temporal relationship with ATG-2, ATG-9, and conjugation machinery. Understanding the precise ordering of ATG-18 recruitment relative to other autophagy factors would clarify its mechanistic role. tags: - caeel-proteostasis - caeel-mitophagy