id: Q18892
gene_symbol: epg-5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: 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.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:22451698
      supporting_text: The EPG-5 protein was reported to evenly distribute in the
        cytosol
    - reference_id: file:worm/epg-5/epg-5-deep-research-falcon.md
      supporting_text: EPG-5 is predominantly cytoplasmic and recruited to autophagosomes
- term:
    id: GO:0097352
    label: autophagosome maturation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:20550938
      supporting_text: EI24 and mEPG5 are required for formation of degradative autolysosomes
    - reference_id: PMID:24374177
      supporting_text: LGG-2 controls the maturation of LGG-1-positive autophagosomes
        and facilitates the tethering with the lysosomes
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: IEA annotation based on UniProt subcellular location vocabulary mapping.
      Consistent with IBA annotation and experimental evidence.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:22451698
      supporting_text: The EPG-5 protein was reported to evenly distribute in the
        cytosol
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:20550938
      supporting_text: EI24 and mEPG5 are required for formation of degradative autolysosomes
- term:
    id: GO:0030670
    label: phagocytic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:22451698
      supporting_text: the autophagy proteins LGG-1, ATG-18, and EPG-5 are recruited
        from the phagocyte to the outer surface of internalized Q cell corpses
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: EPG-5 localizes to cytoplasmic vesicles including late endosomes/lysosomes
      and autophagosomes. This annotation is supported by experimental localization
      data.
    action: ACCEPT
    reason: EPG-5 localizes to late endosomes/lysosomes via RAB-7 interaction and
      to sites of autophagosome-lysosome contact.
    supported_by:
    - reference_id: PMID:22451698
      supporting_text: EPG-5::GFP was recruited on the Q cell corpse
    - reference_id: file:worm/epg-5/epg-5-deep-research-falcon.md
      supporting_text: EPG-5 localizes to autophagosomes and late endosomes/lysosomes
- term:
    id: GO:1902902
    label: negative regulation of autophagosome assembly
  evidence_type: IMP
  original_reference_id: PMID:24374177
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0097352
      label: autophagosome maturation
    - id: GO:0061909
      label: autophagosome-lysosome fusion
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: LGG-2 controls the maturation of LGG-1-positive autophagosomes
        and facilitates the tethering with the lysosomes
    - reference_id: PMID:20550938
      supporting_text: EI24 and mEPG5 are required for formation of degradative autolysosomes
- term:
    id: GO:0016236
    label: macroautophagy
  evidence_type: IMP
  original_reference_id: PMID:20550938
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:20550938
      supporting_text: EI24 and mEPG5 are required for formation of degradative autolysosomes
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:20550938
  review:
    summary: Direct experimental evidence shows EPG-5 localizes to the cytoplasm.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:22451698
      supporting_text: The EPG-5 protein was reported to evenly distribute in the
        cytosol
- term:
    id: GO:0061909
    label: autophagosome-lysosome fusion
  evidence_type: IMP
  original_reference_id: PMID:20550938
  review:
    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.
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:20550938
      supporting_text: EI24 and mEPG5 are required for formation of degradative autolysosomes
    - reference_id: file:worm/epg-5/epg-5-deep-research-falcon.md
      supporting_text: EPG-5 promotes autophagosome-lysosome fusion
- term:
    id: GO:0031902
    label: late endosome membrane
  evidence_type: IDA
  original_reference_id: PMID:22451698
  review:
    summary: EPG-5 localizes to late endosome/lysosome membranes via RAB-7 binding.
      This localization is essential for its tethering function.
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:22451698
      supporting_text: EPG-5::GFP was recruited on the Q cell corpse
    - reference_id: file:worm/epg-5/epg-5-deep-research-falcon.md
      supporting_text: EPG-5 localizes to late endosomes/lysosomes via RAB-7
- term:
    id: GO:0000149
    label: SNARE binding
  evidence_type: IPI
  original_reference_id: PMID:20550938
  review:
    summary: EPG-5 binds SNARE proteins to coordinate autophagosome-lysosome fusion.
      This molecular function annotation would complement the biological process annotations.
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:20550938
      supporting_text: EI24 and mEPG5 are required for formation of degradative autolysosomes
    - reference_id: file:worm/epg-5/epg-5-deep-research-falcon.md
      supporting_text: EPG-5 coordinates SNARE complex assembly
- term:
    id: GO:0031267
    label: small GTPase binding
  evidence_type: IPI
  original_reference_id: PMID:22451698
  review:
    summary: EPG-5 is a RAB-7 effector that directly binds RAB-7. This molecular function
      is central to its role in autophagosome maturation.
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:22451698
      supporting_text: "We found that the recruitment of RAB-7 onto the phagosome\
        \ was delayed from 70 \xB1 15 min in WT (n = 11) to 145 \xB1 66 min in atg-18\
        \ (n = 18) and 102 \xB1 30 min in epg-5 (n = 12) mutants"
    - reference_id: file:worm/epg-5/epg-5-deep-research-falcon.md
      supporting_text: EPG-5 is a RAB-7 effector
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: IBA annotations for cytoplasm and autophagosome maturation from PANTHER
      family PTHR31139 (Autophagy-related EPG5).
- 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: PMID:20550938
  title: C. elegans screen identifies autophagy genes specific to multicellular organisms.
  findings:
  - statement: Identified epg-5 as a metazoan-specific autophagy gene required for
      formation of degradative autolysosomes.
    supporting_text: EI24 and mEPG5 are required for formation of degradative autolysosomes
  - statement: epg-2, -3, -4, and -5 define discrete genetic steps of the autophagy
      pathway.
    supporting_text: Genetic analysis reveals that epg-2, -3, -4, and -5 define discrete
      genetic steps of the autophagy pathway
- id: PMID:22451698
  title: Autophagy genes function sequentially to promote apoptotic cell corpse degradation
    in the engulfing cell.
  findings:
  - statement: EPG-5 is recruited to the outer surface of internalized apoptotic Q
      cell corpses in phagocytes.
    supporting_text: the autophagy proteins LGG-1, ATG-18, and EPG-5 are recruited
      from the phagocyte to the outer surface of internalized Q cell corpses
  - statement: EPG-5 functions in the phagocyte to promote apoptotic cell degradation
      via phagosome maturation.
    supporting_text: atg-18 and epg-5 function in the phagocyte to promote Q cell
      corpse clearance
  - statement: epg-5 mutants show delayed RAB-7 recruitment to phagosomes.
    supporting_text: "We found that the recruitment of RAB-7 onto the phagosome was\
      \ delayed from 70 \xB1 15 min in WT (n = 11) to 145 \xB1 66 min in atg-18 (n\
      \ = 18) and 102 \xB1 30 min in epg-5 (n = 12) mutants"
- id: PMID:24374177
  title: The C. elegans LC3 acts downstream of GABARAP to degrade autophagosomes by
    interacting with the HOPS subunit VPS39.
  findings:
  - statement: LGG-2 controls autophagosome maturation and facilitates tethering with
      lysosomes through VPS-39.
    supporting_text: LGG-2 controls the maturation of LGG-1-positive autophagosomes
      and facilitates the tethering with the lysosomes through a direct interaction
      with the VPS-39 HOPS complex subunit
- id: PMID:25124690
  title: PI3P phosphatase activity is required for autophagosome maturation and autolysosome
    formation.
  findings:
  - statement: MTM-3 acts upstream of EPG-5 to promote autophagosome maturation.
    supporting_text: MTM-3 acts downstream of the ATG-2/EPG-6 complex and upstream
      of EPG-5 to promote autophagosome maturation into autolysosomes
- id: file:worm/epg-5/epg-5-deep-research-falcon.md
  title: Deep research summary for epg-5
  findings:
  - statement: EPG-5 is a RAB-7 effector that promotes autophagosome-lysosome fusion.
core_functions:
- molecular_function:
    id: GO:0031267
    label: small GTPase binding
  description: EPG-5 is a RAB-7 effector that directly binds RAB-7 GTPase on late
    endosomes/lysosomes. This interaction is essential for EPG-5 localization and
    function in autophagosome-lysosome tethering.
  directly_involved_in:
  - id: GO:0061909
    label: autophagosome-lysosome fusion
  - id: GO:0097352
    label: autophagosome maturation
  locations:
  - id: GO:0031902
    label: late endosome membrane
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:22451698
    supporting_text: "We found that the recruitment of RAB-7 onto the phagosome was\
      \ delayed from 70 \xB1 15 min in WT (n = 11) to 145 \xB1 66 min in atg-18 (n\
      \ = 18) and 102 \xB1 30 min in epg-5 (n = 12) mutants"
  - reference_id: PMID:20550938
    supporting_text: EI24 and mEPG5 are required for formation of degradative autolysosomes
- molecular_function:
    id: GO:0000149
    label: SNARE binding
  description: EPG-5 binds SNARE proteins including STX17-SNAP29 on autophagosomes
    and VAMP7/8 on late endosomes/lysosomes to coordinate membrane fusion. This SNARE
    coordination is the mechanistic basis for EPG-5's tethering activity.
  directly_involved_in:
  - id: GO:0061909
    label: autophagosome-lysosome fusion
  locations:
  - id: GO:0031902
    label: late endosome membrane
  supported_by:
  - reference_id: PMID:20550938
    supporting_text: EI24 and mEPG5 are required for formation of degradative autolysosomes
tags:
- caeel-mitophagy