EPG-6 (ectopic PGL granules 6) is the C. elegans member of the WIPI3/WIPI4 (yeast Hsv2) group of PROPPINs, seven-bladed WD40 beta-propeller proteins that bind phosphoinositides. EPG-6 binds PtdIns(3)P (and, in vitro, PtdIns(5)P and more weakly PtdIns(4)P and PtdIns(3,5)P2) through a conserved LRRG motif and binds ATG-2 directly, forming an ATG-2/EPG-6 complex equivalent to the yeast Atg2-Atg18 and human ATG2A-WIPI4 complexes. The complex acts at a late step of autophagosome formation, moving PI3P-positive omegasomes on to closed autophagosomes; epg-6 and atg-2 mutants accumulate enlarged early autophagic structures and fail to degrade protein aggregates such as PGL granules and SQST-1 during embryogenesis. EPG-6 is broadly expressed and cytoplasmic. Its paralog ATG-18 (WIPI1/2 group) also binds PI3P but acts at a distinct step. EPG-6-dependent autophagy also delivers ribosomal RNA and ribosomal proteins to lysosomes for degradation by the RNase RNST-2 under normal growth conditions, a turnover route that supports nucleotide homeostasis during development. Loss of epg-6 also extends adult lifespan, which may reflect a role outside autophagy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000045 autophagosome assembly | IMP PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | ACCEPT | Summary: epg-6 loss-of-function mutants fail to form autophagosomes properly and accumulate enlarged early autophagic structures (omegasome-like), with defective aggrephagy. Reason: Core process. Lu et al. 2011 isolated epg-6 in a screen for autophagy mutants and showed that EPG-6 with ATG-2 drives progression of omegasomes to autophagosomes. Independent work confirms an autophagy block in epg-6(bp242) (Takacs et al. 2019). EPG-6 participates directly, as the PI3P-binding partner that recruits ATG-2, rather than only being required. Supporting Evidence: PMID:21802374 epg-6 and atg-2 regulate progression of omegasomes to autophagosomes, and their loss of function causes accumulation of enlarged early autophagic structures PMID:30871075 we provide evidence that in the absence of either ATG-18 or EPG-6 autophagy was impaired |
| GO:0000045 autophagosome assembly | NAS PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | ACCEPT | Summary: Author statement of the same autophagosome-formation role. Reason: Duplicates the IMP annotation from the same paper; the statement is correct and is the core process for EPG-6. Supporting Evidence: PMID:21802374 epg-6 and atg-2 regulate progression of omegasomes to autophagosomes, and their loss of function causes accumulation of enlarged early autophagic structures |
| GO:0000422 autophagy of mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for autophagy of mitochondrion from the Atg18/WIPI PROPPIN node. Reason: IBA from the PROPPIN family node. EPG-6 is part of the general autophagosome-forming machinery, which is shared by bulk and selective autophagy; no C. elegans study has tested EPG-6 in this specific selective pathway. Supporting Evidence: PMID:21802374 epg-6 and atg-2 regulate progression of omegasomes to autophagosomes, and their loss of function causes accumulation of enlarged early autophagic structures |
| GO:0000425 pexophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for pexophagy from the PROPPIN node (yeast Atg18 donor). Reason: IBA from the PROPPIN family node. EPG-6 is part of the general autophagosome-forming machinery, which is shared by bulk and selective autophagy; no C. elegans study has tested EPG-6 in this specific selective pathway. Supporting Evidence: PMID:21802374 epg-6 and atg-2 regulate progression of omegasomes to autophagosomes, and their loss of function causes accumulation of enlarged early autophagic structures |
| GO:0005515 protein binding | IPI PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | MODIFY | Summary: Direct binding of EPG-6 to ATG-2. Reason: The interaction is well supported (direct binding, Lu et al. 2011) and is conserved in yeast Atg18-Atg2 and human WIPI4-ATG2A. "Protein binding" is uninformative; the activity is better captured as an adaptor that links ATG-2 to PI3P-containing membranes, as also asserted by the IBA for GO:0030674. Complex membership is captured separately as GO:0062079 ATG2-ATG18 complex (NEW). Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:21802374 EPG-6 directly interacts with ATG-2 PMID:30185561 WIPI4 binds to one of the tips, enabling the ATG2A-WIPI4 complex to tether a PI3P-containing vesicle to another PI3P-free vesicle |
| GO:0005737 cytoplasm | IDA PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | ACCEPT | Summary: GFP-tagged EPG-6 is diffusely cytoplasmic in embryonic cells. Reason: Correct but general location; EPG-6 is a soluble cytoplasmic protein that is recruited to PI3P-enriched early autophagic membranes. Supporting Evidence: file:worm/epg-6/epg-6-uniprot.txt Localizes to the cytoplasm of all cells during embryogenesis |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Automated cytoplasm annotation. Reason: Consistent with the IDA annotation from Lu et al. 2011. Supporting Evidence: file:worm/epg-6/epg-6-uniprot.txt Localizes to the cytoplasm of all cells during embryogenesis |
| GO:0010314 phosphatidylinositol-5-phosphate binding | IDA PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | KEEP AS NON CORE | Summary: In vitro lipid binding shows EPG-6 binds PtdIns(5)P as well as PtdIns(3)P. Reason: The in vitro binding is reported by the curated paper (UniProt summarises it as high-affinity binding to PtdIns(3)P and PtdIns(5)P). The physiologically relevant ligand at omegasomes is PtdIns(3)P made by VPS-34; no in vivo role for PtdIns(5)P binding has been shown in C. elegans, so this is kept as a non-core binding property. Supporting Evidence: file:worm/epg-6/epg-6-uniprot.txt Binds to phosphatidylinositols on preautophagosomes, which are early autophagic structures, to promote autophagosome formation |
| GO:0016236 macroautophagy | NAS PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | ACCEPT | Summary: Author statement that EPG-6 acts in macroautophagy. Reason: Correct; macroautophagy is the parent of the more specific autophagosome assembly annotation. Supporting Evidence: PMID:21802374 Here we identified an essential autophagy gene in C. elegans, epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity |
| GO:0030674 protein-macromolecule adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for protein-macromolecule adaptor activity from the PROPPIN node. Reason: PROPPINs are beta-propeller scaffolds that bind PI3P on membranes and bind ATG2 on a separate blade; in the human ATG2A-WIPI4 complex WIPI4 sits at one tip of ATG2A and links it to PI3P-containing membranes. EPG-6 binds ATG-2 directly and binds PI3P, so the adaptor role is supported in C. elegans. Supporting Evidence: PMID:21802374 EPG-6 directly interacts with ATG-2 PMID:30185561 WIPI4 binds to one of the tips, enabling the ATG2A-WIPI4 complex to tether a PI3P-containing vesicle to another PI3P-free vesicle |
| GO:0032266 phosphatidylinositol-3-phosphate binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for PtdIns(3)P binding from the PROPPIN node. Reason: Core activity, directly confirmed for EPG-6 by Lu et al. 2011 (IDA row below). PI3P binding is the defining property of the PROPPIN family. Supporting Evidence: PMID:21802374 Here we identified an essential autophagy gene in C. 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: EPG-6 binds PtdIns(3)P in vitro; the LRRG motif is needed for binding and recruitment. Reason: Core molecular function. This is the activity that recruits EPG-6, and with it ATG-2, to PI3P-enriched omegasomes. Supporting Evidence: PMID:21802374 Here we identified an essential autophagy gene in C. elegans, epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity file:worm/epg-6/epg-6-uniprot.txt Binds to phosphatidylinositols on preautophagosomes, which are early autophagic structures, to promote autophagosome formation |
| GO:0034045 obsolete phagophore assembly site membrane | IBA GO_REF:0000033 | MODIFY | Summary: IBA to the now-obsolete term phagophore assembly site membrane. Reason: GO:0034045 is obsolete (QuickGO, checked 2026-10). EPG-6 is a peripheral membrane protein recruited by PI3P to omegasome/phagophore membranes, so the intended location is the phagophore membrane (GO:7770114), the replacement also used for human ATG2A. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000132136 SUPPORTS TRANSFER The node correctly places PROPPINs on PI3P-rich early autophagic membranes; the defect is only that the propagated term is now obsolete. Proposed replacements: phagophore membrane Supporting Evidence: file:worm/epg-6/epg-6-uniprot.txt Binds to phosphatidylinositols on preautophagosomes, which are early autophagic structures, to promote autophagosome formation PMID:21802374 epg-6 and atg-2 regulate progression of omegasomes to autophagosomes, and their loss of function causes accumulation of enlarged early autophagic structures |
| GO:0034045 obsolete phagophore assembly site membrane | IEA GO_REF:0000044 | MODIFY | Summary: UniProt subcellular-location mapping to the now-obsolete phagophore assembly site membrane term. Reason: Same reasoning as the IBA row; replace with GO:7770114 phagophore membrane. Proposed replacements: phagophore membrane Supporting Evidence: file:worm/epg-6/epg-6-uniprot.txt Binds to phosphatidylinositols on preautophagosomes, which are early autophagic structures, to promote autophagosome formation |
| GO:0034497 protein localization to phagophore assembly site | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for protein localization to phagophore assembly site. Reason: In yeast, Atg18 recruits Atg2 to the PAS. In C. elegans the ATG-2/EPG-6 complex is required for the normal distribution of ATG-9 and ATG-13 at early autophagic structures, so a role in localising other Atg proteins is supported, but this is a consequence of its scaffold activity rather than a separate core process. Supporting Evidence: file:worm/epg-6/epg-6-uniprot.txt Component of the epg-6/atg-2 complex, which is involved in the generation of autophagosomes from omegasomes and in the distribution of atg-9 and atg-13 |
| GO:0044804 nucleophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for nucleophagy from the PROPPIN node (yeast Atg18/Hsv2 donors). Reason: IBA from the PROPPIN family node. EPG-6 is part of the general autophagosome-forming machinery, which is shared by bulk and selective autophagy; no C. elegans study has tested EPG-6 in this specific selective pathway. Supporting Evidence: PMID:21802374 epg-6 and atg-2 regulate progression of omegasomes to autophagosomes, and their loss of function causes accumulation of enlarged early autophagic structures |
| GO:0061723 glycophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for glycophagy from the PROPPIN node. Reason: IBA from the PROPPIN family node. EPG-6 is part of the general autophagosome-forming machinery, which is shared by bulk and selective autophagy; no C. elegans study has tested EPG-6 in this specific selective pathway. Supporting Evidence: PMID:21802374 epg-6 and atg-2 regulate progression of omegasomes to autophagosomes, and their loss of function causes accumulation of enlarged early autophagic structures |
| GO:0070273 phosphatidylinositol-4-phosphate binding | IDA PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | KEEP AS NON CORE | Summary: In vitro, EPG-6 binds PtdIns(4)P weakly. Reason: The curated paper reports weak binding to PtdIns(4)P in vitro. No in vivo role is shown; PtdIns(3)P is the relevant ligand. Supporting Evidence: file:worm/epg-6/epg-6-uniprot.txt (PtdIns(4)P) and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) |
| GO:0080025 phosphatidylinositol-3,5-bisphosphate binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for PtdIns(3,5)P2 binding from the PROPPIN node. Reason: PROPPINs bind PtdIns(3,5)P2 in vitro and yeast Atg18 binds it on the vacuole. EPG-6 binds it only weakly in vitro and acts at PI3P-positive omegasomes, so this is a non-core binding property. Supporting Evidence: file:worm/epg-6/epg-6-uniprot.txt (PtdIns(4)P) and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) |
| GO:0080025 phosphatidylinositol-3,5-bisphosphate binding | IDA PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | KEEP AS NON CORE | Summary: In vitro, EPG-6 binds PtdIns(3,5)P2 weakly. Reason: Weak in vitro binding reported by the curated paper; no in vivo role. Supporting Evidence: file:worm/epg-6/epg-6-uniprot.txt (PtdIns(4)P) and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) |
| GO:0062079 ATG2-ATG18 complex | IPI PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | NEW | Summary: EPG-6 binds ATG-2 directly and forms the C. elegans equivalent of the Atg2-Atg18 complex. Reason: Lu et al. 2011 show direct EPG-6-ATG-2 binding and identical mutant phenotypes, and later work refers to the ATG-2/EPG-6 complex. EPG-6 is the WIPI3/4 (Hsv2) group PROPPIN, the same group that forms the human ATG2A-WIPI4 complex. GO:0062079 is defined from the yeast Atg2-Atg18 complex, and human ATG2A carries it, so this is the matching complex term. Membership is a physical assertion and does not rest on necessity evidence alone. Supporting Evidence: PMID:21802374 EPG-6 directly interacts with ATG-2 PMID:25124690 MTM-3 acts downstream of the ATG-2/EPG-6 complex and upstream of EPG-5 to promote autophagosome maturation into autolysosomes PMID:30185561 WIPI4 binds to one of the tips, enabling the ATG2A-WIPI4 complex to tether a PI3P-containing vesicle to another PI3P-free vesicle |
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Download this section (compressed HTML)Q: Is the lifespan extension of epg-6 mutants independent of autophagy, and if so, which EPG-6 partner or tissue mediates it?
Q: Does C. elegans ATG-2 depend on EPG-6 alone, or also on ATG-18, for recruitment to PI3P-positive membranes in different tissues?
Experiment: Rescue epg-6(bp242) with EPG-6 variants that cannot bind PI3P (LRRG mutant) or cannot bind ATG-2, then score PGL granule and SQST-1 degradation, ATG-2 puncta and lifespan.
Hypothesis: PI3P binding and ATG-2 binding are both required for autophagy, while the lifespan effect separates from one or both.
Type: Separation-of-function rescue
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