egl-1 encodes a short, intrinsically disordered BH3-only apoptosis activator in Caenorhabditis elegans. When transcribed in cells fated to die, EGL-1 binds the BCL2-family survival protein CED-9 and inhibits its sequestration of CED-4, allowing CED-4 to activate the CED-3 caspase. The same CED pathway is reused locally in neurons for EGL-1-dependent elimination of transient presynaptic material. EGL-1 also triggers the CED-3-dependent release of the mitochondrial apoptosis-inducing factor homolog WAH-1 into the cytosol and nucleus, where it promotes apoptotic DNA degradation. egl-1 is controlled transcriptionally; in hermaphrodites the sex-determination factor TRA-1A binds a site downstream of egl-1 and represses it in the HSN neurons, which therefore survive, whereas in males the HSNs die.
Definition: Binding to a pro-survival BCL2-family protein through a BH3-mediated interaction to inhibit that protein from sequestering pro-apoptotic BCL2-family effectors or activators.
Justification: EGL-1, BIM, BID, PUMA, NOXA, and related BH3-only proteins donate BH3 helices to pro-survival BCL2-family proteins and inhibit their anti-apoptotic activity. GO:0051434 BH3 domain binding annotates the groove-side receptor, such as CED-9, and is directionally wrong for the EGL-1-side BH3 ligand.
Parent term: molecular function inhibitor activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:10846174 Disruption of the CED-9.CED-4 complex by EGL-1 is a critical... | MODIFY | Summary: EGL-1 uses its BH3-like helix to bind and inhibit CED-9. Reason: The CED-9 interaction is the core EGL-1 molecular function, but generic protein binding loses the BH3-only ligand mechanism and GO:0051434 BH3 domain binding describes the CED-9 groove side. Replace this row with a BH3-ligand-side inhibitor activity for pro-survival BCL2-family proteins. Proposed replacements: pro-survival BCL2 family protein inhibitor activity Supporting Evidence: PMID:10846174 the inability of EGL-1 to induce the displacement of CED-4 from the CED-9.CED-4 complex PMID:15383288 EGL-1 interface mutants failed to bind to CED-9 or to release CED-4 from the CED-4/CED-9 complex, and were unable to induce cell death in vivo |
| GO:0005515 protein binding | IPI PMID:11027303 Demonstration of the in vivo interaction of key cell death r... | MODIFY | Summary: Second-site EGL-1 suppressors show that EGL-1/CED-9 binding is required in vivo for CED-4 release and cell death. Reason: Structure-guided EGL-1 mutations rescued the ced-9(n1950) BH3-groove defect in vitro and in vivo. The row should capture a BH3-only inhibitor activity toward CED-9 rather than uninformative protein binding. Proposed replacements: pro-survival BCL2 family protein inhibitor activity Supporting Evidence: PMID:11027303 direct physical interaction between EGL-1 and CED-9 is essential for the release of CED-4 and the activation of cell death |
| GO:0005515 protein binding | IPI PMID:15383288 Structural, biochemical, and functional analyses of CED-9 re... | MODIFY | Summary: Structural evidence places the C-terminal EGL-1 helix in the CED-9 groove to release CED-4. Reason: The EGL-1/CED-9 crystal structure and interface mutants directly support the same BH3-ligand-side CED-9 inhibitory function; GO:0005515 should be replaced by a proposed pro-survival BCL2-family protein inhibitor activity. Proposed replacements: pro-survival BCL2 family protein inhibitor activity Supporting Evidence: PMID:15383288 The C-terminal half of EGL-1 is necessary and sufficient for binding to CED-9 and for killing cells |
| GO:0005515 protein binding | IPI PMID:9604928 The C. elegans protein EGL-1 is required for programmed cell... | MODIFY | Summary: The first egl-1 study identified the physical EGL-1/CED-9 interaction and placed egl-1 genetically upstream of ced-9. Reason: The reported interaction is real and core, but should be represented as a BH3-only inhibitor activity toward the pro-survival BCL2 homolog CED-9 rather than as generic protein binding. Proposed replacements: pro-survival BCL2 family protein inhibitor activity Supporting Evidence: PMID:9604928 The EGL-1 and CED-9 proteins interact physically. |
| GO:0005515 protein binding | IPI PMID:9604928 The C. elegans protein EGL-1 is required for programmed cell... | MODIFY | Summary: The same 1998 evidence supports EGL-1 binding to CED-9 through its BH3-like region. Reason: This duplicate CED-9 interaction row is core but generic; a proposed BH3-ligand-side pro-survival BCL2-family protein inhibitor activity is the correct replacement. Proposed replacements: pro-survival BCL2 family protein inhibitor activity Supporting Evidence: PMID:9604928 EGL-1 activates programmed cell death by binding to and directly inhibiting the activity of CED-9 |
| GO:0005739 mitochondrion | IDA PMID:10846174 Disruption of the CED-9.CED-4 complex by EGL-1 is a critical... | ACCEPT | Summary: EGL-1 can localize with CED-9-containing complexes at mitochondria. Reason: Although this assay used heterologous mammalian cells, the observation fits the conserved site at which EGL-1 neutralizes membrane-associated CED-9 and releases CED-4. Supporting Evidence: PMID:10846174 CED-4 and CED-9G169E co-localizes with EGL-1 to the mitochondria in mammalian cells |
| GO:0005829 cytosol | IDA PMID:9837929 Caenorhabditis elegans EGL-1 disrupts the interaction of CED... | UNDECIDED | Summary: The cached abstract shows EGL-1-dependent CED-4 movement but not the exact EGL-1 cytosolic localization assay. Reason: The paper is abstract-only locally and the abstract describes CED-4 redistribution from membranes to cytoplasm after EGL-1 expression; leave the cytosol row unresolved until the full figure and construct context can be checked. Supporting Evidence: PMID:9837929 Expression of EGL-1 resulted in redistribution of CED-4 from intracellular membranes, where it co-localized with CED-9, to the cytoplasm |
| GO:0006915 apoptotic process | IMP PMID:11226309 Programmed cell death mediated by ced-3 and ced-4 protects C... | MODIFY | Summary: Salmonella-induced germline apoptosis uses EGL-1 as a positive regulator of the canonical death pathway. Reason: The host-defense paper measured pathogen-induced germline apoptosis and Salmonella susceptibility; the direct EGL-1 assertion is positive regulation of apoptosis, not the whole apoptotic process. Proposed replacements: positive regulation of apoptotic process Supporting Evidence: PMID:11226309 the egl-1(n1084n3082) loss-of-function mutant also exhibited a reduction in Salmonella -induced germ-line apoptosis |
| GO:0008637 apoptotic mitochondrial changes | IDA PMID:15716954 DRP-1-mediated mitochondrial fragmentation during EGL-1-indu... | KEEP AS NON CORE | Summary: EGL-1 can induce mitochondrial fragmentation during apoptosis. Reason: Mitochondrial fragmentation is an experimentally observed EGL-1/CED-9/DRP-1-linked branch, but the central C. elegans apoptosis function of EGL-1 is CED-9 neutralization and CED-4 release. Supporting Evidence: PMID:15716954 Mitochondrial fragmentation is induced by the BH3-only protein EGL-1 and can be blocked by mutations in the bcl-2-like gene ced-9 |
| GO:0030042 actin filament depolymerization | IMP PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | MODIFY | Summary: EGL-1 acts upstream in the local CED pathway that removes presynaptic material. Reason: The actin-severing effector is GSNL-1 after CED-3 cleavage. EGL-1 loss blocks the pathway upstream, so the supported process is positive regulation of synapse pruning rather than direct actin filament depolymerization by EGL-1. Proposed replacements: positive regulation of synapse pruning Supporting Evidence: PMID:26074078 loss-of-function in pro-apoptotic genes, egl-1 and ced-4, and gain-of-function in the anti-apoptotic gene ced-9 induced elimination defects to a similar degree as ced-3(lf) mutants |
| GO:0031334 positive regulation of protein-containing complex assembly | IDA PMID:16208361 Structure of the CED-4-CED-9 complex provides insights into ... | MODIFY | Summary: EGL-1 promotes apoptotic signaling by releasing CED-4 from CED-9 and allowing CED-4 oligomerization. Reason: Positive regulation of protein-containing complex assembly is too generic for the CED-4 apoptosome step; apoptotic signaling pathway captures the CED-9 release mechanism without inventing a missing C. elegans apoptosome-assembly term. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:16208361 EGL-1 binding induces pronounced conformational changes in CED-9 that result in the dissociation of the CED-4 dimer from CED-9. The released CED-4 dimer further dimerizes to form a tetramer |
| GO:0040034 regulation of development, heterochronic | IGI PMID:25432023 CED-3 caspase acts with miRNAs to regulate non-apoptotic gen... | UNDECIDED | Summary: The miRNA enhancer paper establishes a non-apoptotic CED-3 heterochronic branch, but the cached abstract does not verify EGL-1 participation. Reason: This abstract-only record supports direct CED-3 cleavage of heterochronic and miRNA-associated targets. Keep the EGL-1 IGI row unresolved until the full paper shows how far upstream the canonical EGL-1/CED-9/CED-4 module acts in this non-apoptotic setting. Supporting Evidence: PMID:25432023 We provide evidence for a non-apoptotic function of CED-3 caspase that regulates multiple developmental events through proteolytic inactivation. |
| GO:0043065 positive regulation of apoptotic process | EXP PMID:10846174 Disruption of the CED-9.CED-4 complex by EGL-1 is a critical... | ACCEPT | Summary: EGL-1 positively regulates apoptosis by inhibiting CED-9. Reason: The cited biochemical and genetic evidence directly supports EGL-1 as the upstream BH3-only activator that neutralizes CED-9 and permits CED-4/CED-3 apoptotic signaling. Supporting Evidence: PMID:10846174 the release of CED-4 from the CED-9.CED-4 complex is a necessary step for induction of programmed cell death in C. elegans |
| GO:0043065 positive regulation of apoptotic process | IGI PMID:23431138 Related F-box proteins control cell death in Caenorhabditis ... | ACCEPT | Summary: EGL-1 remains one arm of CED-9 inhibition in the DRE-1/F-box apoptosis study. Reason: DRE-1 was identified as a CED-9-directed apoptosis activator in parallel to EGL-1; this row remains consistent with EGL-1 acting as a positive regulator of the canonical apoptosis pathway. Supporting Evidence: PMID:23431138 DRE-1 functions in parallel to EGL-1, requires CED-9 for activity, and binds to CED-9, suggesting that DRE-1 promotes apoptosis by inactivating CED-9. |
| GO:0043065 positive regulation of apoptotic process | IGI PMID:23431138 Related F-box proteins control cell death in Caenorhabditis ... | ACCEPT | Summary: EGL-1 remains one arm of CED-9 inhibition in the DRE-1/F-box apoptosis study. Reason: The same DRE-1 genetic analysis reinforces EGL-1 as a positive regulator of apoptosis through the CED-9/CED-4/CED-3 pathway. Supporting Evidence: PMID:23431138 EGL-1/BH3-only protein to the antiapoptotic CED-9/BCL2 protein |
| GO:0043065 positive regulation of apoptotic process | IGI PMID:23431138 Related F-box proteins control cell death in Caenorhabditis ... | ACCEPT | Summary: EGL-1 remains one arm of CED-9 inhibition in the DRE-1/F-box apoptosis study. Reason: This duplicate genetic-interaction row is still a supported canonical apoptosis-regulation annotation for EGL-1. Supporting Evidence: PMID:23431138 DRE-1 functions in parallel to EGL-1, requires CED-9 for activity, and binds to CED-9 |
| GO:0043068 positive regulation of programmed cell death | IGI PMID:11027303 Demonstration of the in vivo interaction of key cell death r... | MODIFY | Summary: Second-site suppressors show that EGL-1/CED-9 binding is needed to activate apoptotic cell death. Reason: C. elegans canonical programmed cell death is apoptotic, so this broader programmed-cell-death row should be tightened to positive regulation of apoptotic process. Proposed replacements: positive regulation of apoptotic process Supporting Evidence: PMID:11027303 These results establish that direct physical interaction between EGL-1 and CED-9 is essential for the release of CED-4 and the activation of cell death. |
| GO:0043068 positive regulation of programmed cell death | IMP PMID:11027303 Demonstration of the in vivo interaction of key cell death r... | MODIFY | Summary: The egl-1 suppressor mutants tie CED-9 binding to in vivo cell-killing activity. Reason: The evidence supports the canonical apoptotic pathway specifically; replace positive regulation of programmed cell death with the apoptosis-specific child term. Proposed replacements: positive regulation of apoptotic process Supporting Evidence: PMID:11027303 direct physical interaction between EGL-1 and CED-9 is required in vivo for EGL-1 to induce cell death |
| GO:0043068 positive regulation of programmed cell death | IMP PMID:12874127 The Snail-like CES-1 protein of C. elegans can block the exp... | MODIFY | Summary: NSM sister-cell death depends on EGL-1. Reason: The NSM sister cell undergoes the canonical EGL-1-dependent apoptotic pathway, so positive regulation of apoptotic process is more precise than positive regulation of programmed cell death. Proposed replacements: positive regulation of apoptotic process Supporting Evidence: PMID:12874127 The programmed death of the NSM sister cells is dependent on the cell-death activator EGL-1 |
| GO:0043068 positive regulation of programmed cell death | IMP PMID:9604928 The C. elegans protein EGL-1 is required for programmed cell... | MODIFY | Summary: Loss of egl-1 prevents most C. elegans somatic programmed cell deaths. Reason: The 1998 genetic evidence is the canonical worm apoptosis pathway, so replace the broad programmed-cell-death parent with positive regulation of apoptotic process. Proposed replacements: positive regulation of apoptotic process Supporting Evidence: PMID:9604928 a loss-of-function egl-1 mutation prevents most if not all somatic programmed cell deaths |
| GO:0043231 intracellular membrane-bounded organelle | IDA PMID:9837929 Caenorhabditis elegans EGL-1 disrupts the interaction of CED... | UNDECIDED | Summary: The 1998 localization row needs full-text figure context. Reason: The abstract describes CED-4 leaving intracellular membranes after EGL-1 expression, but not enough detail about EGL-1 localization at intracellular membrane-bounded organelles is cached to adjudicate this exact component row. Supporting Evidence: PMID:9837929 Expression of EGL-1 resulted in redistribution of CED-4 from intracellular membranes, where it co-localized with CED-9, to the cytoplasm |
| GO:0045202 synapse | EXP PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | KEEP AS NON CORE | Summary: EGL-1 localizes to synaptic regions during nonlethal CED-pathway synapse elimination. Reason: This synaptic localization is experimentally observed in RME neurons, where the apoptosis module is reused locally to prune presynaptic material rather than to kill the neuron. Supporting Evidence: PMID:26074078 EGL-1 were enriched at synaptic regions and co-localized with mitochondria |
| GO:0045202 synapse | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The UniProt subcellular-location import matches the experimentally observed synaptic localization. Reason: EGL-1 has a real synaptic-region localization in the nonlethal RME-neuron pruning pathway, but this location is outside its core whole-cell apoptotic function. Supporting Evidence: PMID:26074078 EGL-1 were enriched at synaptic regions and co-localized with mitochondria |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:11226309 Programmed cell death mediated by ced-3 and ced-4 protects C... | MARK AS OVER ANNOTATED | Summary: Salmonella resistance is an organism-level consequence of pathogen-induced germline apoptosis. Reason: Loss of egl-1 reduces Salmonella-induced germline apoptosis and survival, but EGL-1 performs the core CED-9 inhibitory apoptosis step rather than antibacterial defense work. Supporting Evidence: PMID:11226309 both the ced-9(n1950) and the egl-1(n1084n3082) mutants were more susceptible to Salmonella -mediated killing |
| GO:0098793 presynapse | IDA PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | KEEP AS NON CORE | Summary: EGL-1 is presynaptic during RME-neuron synapse pruning. Reason: Presynaptic localization is part of the local, nonlethal CED pathway that eliminates transient presynaptic material and is distinct from EGL-1-driven whole-cell apoptosis. Supporting Evidence: PMID:26074078 we generated transgene reporters labeling CED-3 in motor neurons and EGL-1 in RME neurons, and found that CED-3 and EGL-1 were enriched at synaptic regions and co-localized with mitochondria |
| GO:1902742 apoptotic process involved in development | IMP PMID:20713707 Six and Eya promote apoptosis through direct transcriptional... | ACCEPT | Summary: egl-1 expression is required for the developmental apoptosis of the M4 sister cell. Reason: The row captures a developmental instance of the canonical EGL-1 apoptotic program; CEH-34/EYA-1 transcriptionally activate egl-1 in the M4 sister cell so it dies. Supporting Evidence: PMID:20713707 Expression of the proapoptotic gene egl-1 in the M4 sister cell requires ceh-34 and eya-1 function. |
| GO:1902742 apoptotic process involved in development | IMP PMID:22801495 Programmed elimination of cells by caspase-independent cell ... | KEEP AS NON CORE | Summary: The PIG-1 cell-extrusion paper uses egl-1 loss to block canonical apoptosis and reveal an alternative shedding pathway. Reason: PMID:22801495 uses egl-1 loss to expose PAR-4/PIG-1-dependent shedding as a backup route, so it is weak and redundant support for GO:1902742 rather than evidence that the term itself overshoots EGL-1. Supporting Evidence: PMID:22801495 Embryos with a loss-of-function mutation in the Apaf-1 homolog ced-4 or the BH3 domain-encoding gene egl-1 or a gain-of-function mutation of the bcl-2 homolog ced-9 also produced shed cells |
| GO:1904747 positive regulation of apoptotic process involved in development | IGI PMID:23505386 Both the caspase CSP-1 and a caspase-independent pathway pro... | ACCEPT | Summary: The CSP-1 combinatorial genetics keeps EGL-1 in the canonical developmental apoptosis pathway. Reason: The paper distinguishes CSP-1 and caspase-independent branches from canonical EGL-1/CED-9/CED-4/CED-3 signaling; the row remains a valid developmental apoptosis-regulation annotation for EGL-1. Supporting Evidence: PMID:23505386 We conclude that both caspase-dependent and caspase-independent pathways promote apoptotic programmed cell death and the phagocytosis of cell corpses in parallel to the canonical apoptosis pathway involving CED-3 activation. |
| GO:1905808 positive regulation of synapse pruning | IMP PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | KEEP AS NON CORE | Summary: EGL-1 promotes local synapse pruning through the CED pathway in neurons. Reason: This is a direct but specialized non-apoptotic reuse of the EGL-1/CED-9/CED-4/CED-3 pathway in RME and DD neurons. Supporting Evidence: PMID:26074078 We find that the conserved apoptotic cell death (CED) pathway and axonal mitochondria are required for the elimination of transiently formed clusters of presynaptic components in RME neurons. |
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Download this section (compressed HTML)Q: Should GO add a BH3-ligand-side molecular-function term for EGL-1 and mammalian BH3-only proteins, paired with the existing groove-side BH3 domain binding term?
Q: Should local reuse of EGL-1, CED-9, CED-4, and CED-3 in synapse pruning be curated in a worm-specific pathway module distinct from whole-cell apoptosis?
Q: Does EGL-1 participate directly in the CED-3/miRNA heterochronic pathway, or are egl-1 genetic interactions in that paper indirect consequences of upstream apoptosis-module perturbation?
Experiment: Endogenously introduce EGL-1 BH3 interface mutations that abolish or weaken CED-9 binding, then quantify embryonic cell-corpse formation, M4/NSM sister-cell survival, CED-4 release or CED-3 activation, and RME/DD presynaptic-material pruning in the same allelic series.
Hypothesis: The same EGL-1 BH3/CED-9 interface is required for whole-cell apoptosis and for local CED-pathway synapse pruning.
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