EPG-5 (Ectopic P granules protein 5) is a metazoan-specific autophagy tethering factor that functions as a RAB-7 effector to determine the fusion specificity of autophagosomes with late endosomes/lysosomes. EPG-5 binds RAB-7 on late endosomes/lysosomes and engages LGG-1 (C. elegans LC3/ATG8 ortholog) via conserved LIR motifs on autophagosomes. It coordinates the STX17-SNAP29-VAMP7/8 trans-SNARE machinery to promote correct autophagosome-lysosome fusion and prevent aberrant SNARE pairing. Loss of epg-5 causes accumulation of non-degradative hybrid vesicles bearing both autophagosomal and endosomal markers, impaired lysosomal acidification, and defective autophagy flux. EPG-5 also functions in LAP (LC3-associated phagocytosis) to promote delivery of engulfed apoptotic cells to lysosomes. Human ortholog EPG5 mutations cause Vici syndrome, a severe multisystem disorder.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: EPG-5 is localized to the cytoplasm with partial localization to late endosome/lysosome membranes and autophagosome-lysosome contact sites. The IBA annotation is consistent with the general cytoplasmic distribution of this protein. Reason: EPG-5 is a cytoplasmic protein that is recruited to late endosomes/lysosomes via RAB-7 interaction. The cytoplasm annotation accurately reflects the general localization of EPG-5 before it is recruited to specific membrane compartments for its fusion-tethering function. Supporting Evidence: PMID:22451698 The EPG-5 protein was reported to evenly distribute in the cytosol file:worm/epg-5/epg-5-deep-research-falcon.md EPG-5 is predominantly cytoplasmic and recruited to autophagosomes |
| GO:0097352 autophagosome maturation | IBA GO_REF:0000033 | ACCEPT | Summary: EPG-5 is essential for autophagosome maturation, functioning as a RAB-7 effector that determines fusion specificity of autophagosomes with late endosomes/lysosomes. This is a core function of the protein conserved across metazoans. Reason: Autophagosome maturation is a core function of EPG-5. The protein acts as a tethering factor that binds RAB-7 on late endosomes/lysosomes and LGG-1 on autophagosomes, coordinating SNARE-mediated fusion. epg-5 mutants accumulate non-degradative autolysosomes indicating impaired maturation. Supporting Evidence: PMID:20550938 EI24 and mEPG5 are required for formation of degradative autolysosomes PMID:24374177 LGG-2 controls the maturation of LGG-1-positive autophagosomes and facilitates the tethering with the lysosomes |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location vocabulary mapping. Consistent with IBA annotation and experimental evidence. Reason: This annotation is correct and consistent with the IBA annotation and experimental evidence. It is acceptable to retain both IBA and IEA annotations for the same term. Supporting Evidence: PMID:22451698 The EPG-5 protein was reported to evenly distribute in the cytosol |
| GO:0006914 autophagy | IEA GO_REF:0000043 | ACCEPT | Summary: EPG-5 is involved in autophagy, specifically in the late autophagosome maturation/fusion step. This IEA annotation from UniProt keyword mapping is correct but more general than the specific function (autophagosome maturation). Reason: While GO:0097352 (autophagosome maturation) is more specific for EPG-5's function, the parent term GO:0006914 (autophagy) is not incorrect. The IEA annotation provides a valid broader annotation that complements the more specific IBA annotation. Supporting Evidence: PMID:20550938 EI24 and mEPG5 are required for formation of degradative autolysosomes |
| GO:0030670 phagocytic vesicle membrane | IEA GO_REF:0000044 | ACCEPT | Summary: EPG-5 localizes to phagosome membranes of engulfed apoptotic cells during LAP (LC3-associated phagocytosis). This is supported by experimental evidence in PMID:22451698. Reason: EPG-5::GFP was recruited to the outer surface of internalized apoptotic Q cell corpses in the phagocyte. This localization is distinct from its role in canonical autophagy but represents a genuine function in apoptotic cell clearance via LAP. Supporting Evidence: PMID:22451698 the autophagy proteins LGG-1, ATG-18, and EPG-5 are recruited from the phagocyte to the outer surface of internalized Q cell corpses |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000043 | ACCEPT | Summary: EPG-5 localizes to cytoplasmic vesicles including late endosomes/lysosomes and autophagosomes. This annotation is supported by experimental localization data. Reason: EPG-5 localizes to late endosomes/lysosomes via RAB-7 interaction and to sites of autophagosome-lysosome contact. Supporting Evidence: PMID:22451698 EPG-5::GFP was recruited on the Q cell corpse file:worm/epg-5/epg-5-deep-research-falcon.md EPG-5 localizes to autophagosomes and late endosomes/lysosomes |
| GO:1902902 negative regulation of autophagosome assembly | IMP PMID:24374177 The C. elegans LC3 acts downstream of GABARAP to degrade aut... | MODIFY | Summary: This annotation suggests EPG-5 negatively regulates autophagosome assembly. However, EPG-5 functions at the autophagosome maturation step, not assembly. The observed increase in autophagosomes in epg-5 mutants is due to blocked fusion/degradation, not increased assembly rate. Reason: The annotation appears to be based on the observation that epg-5 mutants cause accumulation of autophagosomes. However, this accumulation results from impaired autophagosome-lysosome fusion and degradation, not from increased autophagosome formation. EPG-5 acts downstream at the maturation step. The correct interpretation is that EPG-5 is involved in autophagosome maturation (GO:0097352) or autophagosome-lysosome fusion (GO:0061909). The term GO:1902902 misrepresents the mechanism. Proposed replacements: autophagosome maturation autophagosome-lysosome fusion Supporting Evidence: PMID:24374177 LGG-2 controls the maturation of LGG-1-positive autophagosomes and facilitates the tethering with the lysosomes PMID:20550938 EI24 and mEPG5 are required for formation of degradative autolysosomes |
| GO:0016236 macroautophagy | IMP PMID:20550938 C. elegans screen identifies autophagy genes specific to mul... | ACCEPT | Summary: EPG-5 is essential for macroautophagy, specifically the maturation step where autophagosomes fuse with lysosomes. This is a core function supported by the seminal study that identified epg-5. Reason: PMID:20550938 identified epg-5 in a genetic screen for autophagy genes and demonstrated that it is required for starvation-induced autophagy. While autophagosome maturation is the more specific step, macroautophagy accurately describes the broader process in which EPG-5 functions. Supporting Evidence: PMID:20550938 EI24 and mEPG5 are required for formation of degradative autolysosomes |
| GO:0005737 cytoplasm | IDA PMID:20550938 C. elegans screen identifies autophagy genes specific to mul... | ACCEPT | Summary: Direct experimental evidence shows EPG-5 localizes to the cytoplasm. Reason: This IDA annotation provides the strongest evidence for cytoplasmic localization. EPG-5 is a cytoplasmic protein that is recruited to late endosome/lysosome membranes for its fusion function. Supporting Evidence: PMID:22451698 The EPG-5 protein was reported to evenly distribute in the cytosol |
| GO:0061909 autophagosome-lysosome fusion | IMP PMID:20550938 C. elegans screen identifies autophagy genes specific to mul... | NEW | Summary: EPG-5 is a tethering factor that directly promotes autophagosome-lysosome fusion by coordinating RAB-7, LGG-1/LC3, and SNARE proteins. This is the most specific term for EPG-5's core molecular function. Reason: PMID:20550938 demonstrated that EPG-5 is required for formation of degradative autolysosomes. Later work definitively established that EPG-5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. This term should be added with IMP evidence. Supporting Evidence: PMID:20550938 EI24 and mEPG5 are required for formation of degradative autolysosomes file:worm/epg-5/epg-5-deep-research-falcon.md EPG-5 promotes autophagosome-lysosome fusion |
| GO:0031902 late endosome membrane | IDA PMID:22451698 Autophagy genes function sequentially to promote apoptotic c... | NEW | Summary: EPG-5 localizes to late endosome/lysosome membranes via RAB-7 binding. This localization is essential for its tethering function. Reason: EPG-5 is recruited to late endosomes/lysosomes via its interaction with RAB-7. This localization is distinct from the general cytoplasm annotation and more accurately reflects the site of EPG-5's action. Supporting Evidence: PMID:22451698 EPG-5::GFP was recruited on the Q cell corpse file:worm/epg-5/epg-5-deep-research-falcon.md EPG-5 localizes to late endosomes/lysosomes via RAB-7 |
| GO:0000149 SNARE binding | IPI PMID:20550938 C. elegans screen identifies autophagy genes specific to mul... | NEW | Summary: EPG-5 binds SNARE proteins to coordinate autophagosome-lysosome fusion. This molecular function annotation would complement the biological process annotations. Reason: EPG-5 engages the autophagosomal Qabc SNARE complex STX17-SNAP29 and coordinates with the R-SNARE VAMP7/8 on late endosomes/lysosomes. SNARE binding is a core molecular function that enables EPG-5's tethering activity. Supporting Evidence: PMID:20550938 EI24 and mEPG5 are required for formation of degradative autolysosomes file:worm/epg-5/epg-5-deep-research-falcon.md EPG-5 coordinates SNARE complex assembly |
| GO:0031267 small GTPase binding | IPI PMID:22451698 Autophagy genes function sequentially to promote apoptotic c... | NEW | Summary: EPG-5 is a RAB-7 effector that directly binds RAB-7. This molecular function is central to its role in autophagosome maturation. Reason: EPG-5 binds RAB-7 (a small GTPase of the Rab family) on late endosomes/lysosomes. This interaction is essential for EPG-5 localization and function. RAB-7 binding is a core molecular function of EPG-5. Supporting Evidence: PMID:22451698 We found that the recruitment of RAB-7 onto the phagosome was delayed from 70 ± 15 min in WT (n = 11) to 145 ± 66 min in atg-18 (n = 18) and 102 ± 30 min in epg-5 (n = 12) mutants file:worm/epg-5/epg-5-deep-research-falcon.md EPG-5 is a RAB-7 effector |
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