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.
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".
Parent term: membrane
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0032266 phosphatidylinositol-3-phosphate binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation based on phylogenetic inference from WIPI family proteins. ATG-18 binds PI3P via its conserved FRRG motif (PMID:21802374, PMID:22451698). 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). Supporting Evidence: PMID:21802374 ATG-18, plays a distinct role in autophagosome formation PMID:22451698 FRRG (amino acids 227-230) in ATG-18 was identified as the PI(3)P binding site file:worm/atg-18/atg-18-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0034045 phagophore assembly site membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA annotation indicating localization to early autophagic structures. Consistent with WIPI family function at omegasomes/phagophores. 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 Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000132136 · Atg18/WIPI PROPPIN ancestral node SUPPORTS TRANSFER 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. UniProtKB:Q9Y4P8 · WIPI2 (human) SOURCE WEAK OR INFERRED Seed carries the same defective term, so the propagation adds no independent evidence for a PAS membrane. Supporting Evidence: PMID:21802374 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 |
| GO:0000422 autophagy of mitochondrion | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:30133321 Nonselective autophagy reduces mitochondrial content during starvation in Caenorhabditis elegans |
| GO:0000425 pexophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation based on yeast Atg18 function in pexophagy. No direct C. elegans experimental evidence available. 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. |
| GO:0030674 protein-macromolecule adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation reflecting the adaptor function of WIPI proteins that bridge PI3P-containing membranes to downstream autophagy machinery. 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). Supporting Evidence: PMID:22451698 EPG-5 and ATG-18 are required for RAB-5 recruitment |
| GO:0044804 nucleophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation based on yeast Atg18 function. No direct C. elegans experimental evidence for nucleophagy. Reason: Phylogenetically inferred but not directly demonstrated in C. elegans. Nucleophagy is not a well-characterized process in nematodes. |
| GO:0061723 glycophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation based on Drosophila evidence. No direct C. elegans experimental evidence for glycophagy. 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. |
| GO:0034497 protein localization to phagophore assembly site | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation reflecting role in recruiting proteins to nascent autophagosomes. Consistent with WIPI family function. 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. Supporting Evidence: PMID:21802374 We also established the hierarchical relationship of autophagy genes in degradation of protein aggregates |
| GO:0080025 phosphatidylinositol-3,5-bisphosphate binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation consistent with known PROPPIN binding to PI(3,5)P2. Also supported by IDA evidence (PMID:21802374). 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). Supporting Evidence: PMID:21802374 elegans, epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cytosolic localization. ATG-18 is cytosolic when not recruited to membranes. 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. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from UniProt subcellular location. Broader than cytosol annotation but accurate. Reason: General localization is correct. Supported by IDA evidence (PMID:25124690) showing cytoplasmic localization. |
| GO:0006914 autophagy | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation from UniProt keyword mapping. Core function of ATG-18 is in autophagy. Reason: Core biological process. Extensively validated by experimental evidence (PMID:12958363, PMID:21802374, PMID:22451698). ATG-18 is a canonical autophagy gene. Supporting Evidence: PMID:12958363 autophagy is a cellular pathway essential for dauer development and life-span extension in C. elegans |
| GO:0008289 lipid binding | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: IEA annotation from UniProt keyword. Accurate but less specific than the phosphoinositide binding annotations. 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. |
| GO:0030670 phagocytic vesicle membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation from UniProt subcellular location. ATG-18 is recruited to phagosomal membranes during apoptotic cell degradation. 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. Supporting Evidence: PMID:22451698 Both GFP::ATG-18 and EPG-5::GFP appeared on the outer surface of apoptotic Q cells even more prominently than LGG-1::GFP |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation from UniProt keyword. General vesicle localization. Reason: Accurate general localization. ATG-18 localizes to autophagosomes and phagosomes, which are cytoplasmic vesicles. |
| GO:0097237 cellular response to toxic substance | IMP PMID:27875098 HLH-30/TFEB-mediated autophagy functions in a cell-autonomou... | ACCEPT | 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). 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. Supporting Evidence: PMID:27875098 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 |
| GO:0001778 plasma membrane repair | IMP PMID:27875098 HLH-30/TFEB-mediated autophagy functions in a cell-autonomou... | ACCEPT | 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). 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. Supporting Evidence: PMID:27875098 autophagy also contributes to the intrinsic membrane pore-repair to defend against Cry5B PFT intoxication |
| GO:0098792 xenophagy | IMP PMID:27875098 HLH-30/TFEB-mediated autophagy functions in a cell-autonomou... | ACCEPT | 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). 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). Supporting Evidence: PMID:27875098 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 |
| GO:0036093 germ cell proliferation | IMP PMID:28285998 A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordin... | KEEP AS NON CORE | Summary: IMP annotation showing atg-18 is required for late larval expansion of germline stem cell progenitors (PMID:28285998). 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). Supporting Evidence: PMID:28285998 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 |
| GO:0042078 germ-line stem cell division | IMP PMID:28285998 A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordin... | KEEP AS NON CORE | Summary: IMP annotation showing atg-18 promotes cell-cycle progression in germline stem cells (PMID:28285998). 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). Supporting Evidence: PMID:28285998 Similar to DAF-2/IIR, BEC-1/BECN1/Beclin1, ATG-18/WIPI1/2, and ATG-16.2/ATG16L all promote cell-cycle progression |
| GO:0005737 cytoplasm | IDA PMID:25124690 PI3P phosphatase activity is required for autophagosome matu... | ACCEPT | Summary: IDA annotation based on direct localization studies showing ATG-18 in the cytoplasm (PMID:25124690). 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). Supporting Evidence: PMID:25124690 loss of MTM-3 causes increased autophagic association of ATG-18 in a PtdIns3P-dependent manner |
| GO:0010508 positive regulation of autophagy | IMP PMID:25124690 PI3P phosphatase activity is required for autophagosome matu... | ACCEPT | Summary: IMP annotation showing ATG-18 promotes autophagy. ATG-18 functions downstream of PI3K and is required for autophagosome formation. 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). Supporting Evidence: PMID:25124690 MTM-3 acts downstream of the ATG-2/EPG-6 complex... to promote autophagosome maturation into autolysosomes |
| GO:0045335 phagocytic vesicle | IDA PMID:22451698 Autophagy genes function sequentially to promote apoptotic c... | ACCEPT | Summary: IDA annotation showing ATG-18 localizes to phagocytic vesicles containing apoptotic cells (PMID:22451698). 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. Supporting Evidence: PMID:22451698 Both GFP::ATG-18 and EPG-5::GFP appeared on the outer surface of apoptotic Q cells even more prominently than LGG-1::GFP |
| GO:0009792 embryo development ending in birth or egg hatching | IGI PMID:21502138 Shared developmental roles and transcriptional control of au... | KEEP AS NON CORE | Summary: IGI annotation indicating genetic interaction with ced genes during embryonic development. Autophagy and apoptosis show redundant roles in embryogenesis. Reason: Developmental phenotype showing genetic interaction. Not a core molecular function of ATG-18 but reflects its role in autophagy which has developmental consequences. Supporting Evidence: PMID:21502138 Shared developmental roles and transcriptional control of autophagy and apoptosis in Caenorhabditis elegans. |
| GO:0008340 determination of adult lifespan | IGI PMID:21906946 Autophagy and lipid metabolism coordinately modulate life sp... | KEEP AS NON CORE | Summary: IGI annotation showing atg-18 genetic interaction in lifespan regulation. Autophagy contributes to longevity in C. elegans. 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. Supporting Evidence: PMID:21906946 2011 Sep 8. Autophagy and lipid metabolism coordinately modulate life span in germline-less C. |
| GO:0010314 phosphatidylinositol-5-phosphate binding | IDA PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | ACCEPT | 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). Reason: Core molecular function demonstrated by direct binding assays. The FRRG motif mediates binding to multiple phosphoinositides including PI5P. Supporting Evidence: PMID:21802374 elegans, epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity |
| GO:0032266 phosphatidylinositol-3-phosphate binding | IDA PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | ACCEPT | Summary: IDA annotation demonstrating direct PI3P binding via the FRRG motif. Primary molecular function of ATG-18 for membrane recruitment. 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). Supporting Evidence: PMID:22451698 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:21802374 2011 Jul 28. The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes. |
| GO:0070273 phosphatidylinositol-4-phosphate binding | IDA PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | ACCEPT | Summary: IDA annotation showing ATG-18 binds PI4P. UniProt confirms binding to "phosphatidylinositol 4-phosphate (PtdIns(4)P)" (PMID:21802374). Reason: Core molecular function demonstrated by direct binding assays. The broad phosphoinositide specificity is characteristic of PROPPIN proteins. Supporting Evidence: PMID:21802374 epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity |
| GO:0080025 phosphatidylinositol-3,5-bisphosphate binding | IDA PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | ACCEPT | Summary: IDA annotation demonstrating PI(3,5)P2 binding. ATG-18 binds "more weakly to phosphatidylinositol 3,5-bisphosphate" compared to PI3P. Reason: Core molecular function. Weaker binding than to PI3P but demonstrated experimentally. Duplicates IBA annotation with direct evidence. Supporting Evidence: PMID:21802374 epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity |
| GO:0043277 apoptotic cell clearance | IMP PMID:21183797 The Atg6/Vps30/Beclin 1 ortholog BEC-1 mediates endocytic re... | ACCEPT | 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). 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. Supporting Evidence: PMID:21183797 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 |
| GO:0048598 embryonic morphogenesis | IGI PMID:21285529 Autophagy and apoptosis are redundantly required for C. eleg... | KEEP AS NON CORE | Summary: IGI annotation indicating genetic interaction with ced genes during embryonic morphogenesis. Reason: Developmental phenotype reflecting pleiotropic effects of autophagy deficiency. Not a core molecular function. Supporting Evidence: PMID:21285529 Autophagy and apoptosis are redundantly required for C. |
| GO:0012501 programmed cell death | IGI PMID:17901876 Autophagy is required for necrotic cell death in Caenorhabdi... | KEEP AS NON CORE | Summary: IGI annotation showing genetic interaction with cell death genes. Autophagy is required for necrotic cell death. 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. Supporting Evidence: PMID:17901876 2007 Sep 28. Autophagy is required for necrotic cell death in Caenorhabditis elegans. |
| GO:0030163 protein catabolic process | IMP PMID:17172799 Autophagy genes protect against disease caused by polyglutam... | ACCEPT | Summary: IMP annotation showing autophagy genes including atg-18 promote clearance of polyglutamine protein aggregates (PMID:17172799). 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. Supporting Evidence: PMID:17172799 genetic inactivation of autophagy genes accelerates the accumulation of polyQ40 aggregates in C. elegans muscle cells and exacerbates polyQ40-induced muscle dysfunction |
| GO:0006914 autophagy | IGI PMID:12958363 Autophagy genes are essential for dauer development and life... | ACCEPT | Summary: IGI annotation showing atg-18 functions with other autophagy genes including daf-2 in autophagy during dauer formation (PMID:12958363). 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). Supporting Evidence: PMID:12958363 Dauer formation is associated with increased autophagy and also requires C. elegans orthologs of the yeast autophagy genes APG1, APG7, APG8, and AUT10 |
| GO:0040024 dauer larval development | IGI PMID:12958363 Autophagy genes are essential for dauer development and life... | ACCEPT | Summary: IGI annotation showing atg-18 is required for proper dauer formation in daf-2 mutants (PMID:12958363). 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). Supporting Evidence: PMID:12958363 autophagy is a cellular pathway essential for dauer development and life-span extension in C. elegans |
Loading supporting content…
Download this section (compressed HTML)Q: 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.
Q: 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.
Experiment: 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.
Experiment: 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.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)