CED-9 is the Caenorhabditis elegans BCL2-family apoptosis inhibitor that restrains the core EGL-1/CED-9/CED-4/CED-3 death pathway at mitochondria and other intracellular membranes. CED-9 binds and sequesters an asymmetric CED-4 dimer, preventing CED-4 apoptosome assembly and CED-3 caspase activation; the BH3-only protein EGL-1 binds CED-9 to release CED-4 and initiate apoptosis. CED-9 is also reused locally in developmental synapse pruning and has reported, context-dependent roles in mitochondrial fission/fusion control through DRP-1 and FZO-1.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000423 mitophagy | IMP PMID:25896323 Coordination of mitophagy and mitochondrial biogenesis durin... | UNDECIDED | Summary: DCT-1 is the demonstrated mitophagy effector in this abstract; the cached record does not expose the CED-9-specific evidence behind the row. Reason: The paper is relevant to C. elegans mitophagy, but the visible abstract names DCT-1 and SKN-1 rather than CED-9. Leave the CED-9 mitophagy claim to full-text WormBase review. Supporting Evidence: PMID:25896323 We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans. |
| GO:0001836 release of cytochrome c from mitochondria | IBA GO_REF:0000033 | REMOVE | Summary: Release of cytochrome c from mitochondria is mammalian BCL2-family biology and is not the CED-9 trigger for CED-4/CED-3 activation in worms. Reason: PAINT propagates this BAX/BAK/BCL2-family mitochondrial permeabilization term from mammalian sources at a broad BCL2-related node. CED-9 instead restrains the Apaf-1-like adaptor CED-4 directly, and CED-4 is released by EGL-1 rather than by cytochrome c. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000135648 · BCL-2-related family ancestral node SUPPORTS SOURCE BUT NOT TARGET PTN000135648 carries mammalian MOMP and cytochrome-c-release assertions on the same node as worm CED-9. Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. 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. |
| GO:0005096 GTPase activator activity | IDA PMID:18827010 CED-9 and mitochondrial homeostasis in C. elegans muscle. | KEEP AS NON CORE | Summary: CED-9 can activate human DRP1 GTPase in vitro in a mitochondrial-dynamics branch. Reason: The GTPase-activator activity is experimentally reported but tied to mitochondrial fission/fusion control, not to the core EGL-1/CED-9/CED-4/CED-3 apoptosis switch. Supporting Evidence: PMID:18827010 CED-9 activates the GTPase activity of human DRP1 |
| GO:0005515 protein binding | IPI PMID:10101135 C. elegans MAC-1, an essential member of the AAA family of A... | REMOVE | Summary: The MAC-1/CED-4 paper supports a CED-4-centered anti-death complex that may include CED-9, but the row is only generic protein binding. Reason: This generic binding assertion does not describe CED-9's core sequestering activity toward CED-4 and is not enough to define a specific CED-9 molecular function toward the CED-4 isoform. Supporting Evidence: PMID:10101135 Furthermore, MAC-1 can form a multi-protein complex that also includes CED-3 or CED-9. |
| GO:0005515 protein binding | IPI PMID:10101135 C. elegans MAC-1, an essential member of the AAA family of A... | REMOVE | Summary: MAC-1 can be in a complex with CED-4 and CED-9, but this is a generic interaction row. Reason: The row is not the direct CED-9 anti-apoptotic activity, and the cached abstract does not establish a sharper CED-9 molecular function for MAC-1. Supporting Evidence: PMID:10101135 Furthermore, MAC-1 can form a multi-protein complex that also includes CED-3 or CED-9. |
| GO:0005515 protein binding | IPI PMID:10846174 Disruption of the CED-9.CED-4 complex by EGL-1 is a critical... | MODIFY | Summary: The cited EGL-1 interaction is the BH3-only input that neutralizes CED-9 and releases CED-4. Reason: Replace generic protein binding with BH3 domain binding, the specific molecular recognition event by which CED-9 senses EGL-1 and changes conformation to release CED-4. Proposed replacements: BH3 domain binding Supporting Evidence: PMID:10846174 We find that CED-9G169E retains the ability to bind both EGL-1 and CED-4, although its affinity for EGL-1 is reduced. 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. |
| GO:0005515 protein binding | IPI PMID:10846174 Disruption of the CED-9.CED-4 complex by EGL-1 is a critical... | MODIFY | Summary: CED-9 binds and sequesters CED-4, preventing apoptosome-mediated CED-3 activation until EGL-1 relieves the inhibition. Reason: The interaction with CED-4 is biologically a protein-sequestering activity: CED-9 holds the CED-4 dimer inactive and thereby blocks CED-4 oligomerization and CED-3 autoactivation. Generic protein binding should be narrowed to that activity. Proposed replacements: protein sequestering 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:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0005515 protein binding | IPI PMID:11027303 Demonstration of the in vivo interaction of key cell death r... | MODIFY | Summary: CED-9 binds and sequesters CED-4, preventing apoptosome-mediated CED-3 activation until EGL-1 relieves the inhibition. Reason: The interaction with CED-4 is biologically a protein-sequestering activity: CED-9 holds the CED-4 dimer inactive and thereby blocks CED-4 oligomerization and CED-3 autoactivation. Generic protein binding should be narrowed to that activity. Proposed replacements: protein sequestering activity 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. PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0005515 protein binding | IPI PMID:11027303 Demonstration of the in vivo interaction of key cell death r... | MODIFY | Summary: The cited EGL-1 interaction is the BH3-only input that neutralizes CED-9 and releases CED-4. Reason: Replace generic protein binding with BH3 domain binding, the specific molecular recognition event by which CED-9 senses EGL-1 and changes conformation to release CED-4. Proposed replacements: BH3 domain binding 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. 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. |
| GO:0005515 protein binding | IPI PMID:11114722 The C. elegans orthologue ceBNIP3 interacts with CED-9 and C... | REMOVE | Summary: The ceBNIP3/DCT-1 interaction was detected in heterologous mammalian-cell experiments and does not define core CED-9 activity. Reason: The row is uninformative generic protein binding; the abstracts do not justify a specific direct CED-9 molecular function for DCT-1. Supporting Evidence: PMID:11114722 ceBNIP3 protein interacts with CED-9 and BCL-XL, but unlike other pro-apoptotic BCL-2 family members, the BH3-like domain does not participate in dimerization. |
| GO:0005515 protein binding | IPI PMID:14555965 Mutational analysis of the interacting cell death regulators... | MODIFY | Summary: CED-9 binds and sequesters CED-4, preventing apoptosome-mediated CED-3 activation until EGL-1 relieves the inhibition. Reason: The interaction with CED-4 is biologically a protein-sequestering activity: CED-9 holds the CED-4 dimer inactive and thereby blocks CED-4 oligomerization and CED-3 autoactivation. Generic protein binding should be narrowed to that activity. Proposed replacements: protein sequestering activity Supporting Evidence: PMID:14555965 Here we confirm that CED-9 and CED-4 interact and using a series of deletion mutants, demonstrate that only short N-terminal deletions are tolerated in each molecule without loss-of-interaction. PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0005515 protein binding | IPI PMID:15383288 Structural, biochemical, and functional analyses of CED-9 re... | MODIFY | Summary: The cited EGL-1 interaction is the BH3-only input that neutralizes CED-9 and releases CED-4. Reason: Replace generic protein binding with BH3 domain binding, the specific molecular recognition event by which CED-9 senses EGL-1 and changes conformation to release CED-4. Proposed replacements: BH3 domain binding Supporting Evidence: PMID:15383288 Structure of the EGL-1/CED-9 complex revealed that EGL-1 adopts an extended alpha-helical conformation and induces substantial structural rearrangements in CED-9 upon binding. 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. |
| GO:0005515 protein binding | IPI PMID:16208361 Structure of the CED-4-CED-9 complex provides insights into ... | MODIFY | Summary: CED-9 binds and sequesters CED-4, preventing apoptosome-mediated CED-3 activation until EGL-1 relieves the inhibition. Reason: The interaction with CED-4 is biologically a protein-sequestering activity: CED-9 holds the CED-4 dimer inactive and thereby blocks CED-4 oligomerization and CED-3 autoactivation. Generic protein binding should be narrowed to that activity. Proposed replacements: protein sequestering activity Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0005515 protein binding | IPI PMID:18776901 Inhibition of CED-3 zymogen activation and apoptosis in Caen... | REMOVE | Summary: This CSP-3 paper used CED-9 as an in vitro CED-3 substrate/control rather than establishing a direct CED-9 binding activity toward CED-3. Reason: The paper characterizes CSP-3 inhibition of CED-3 autoactivation, while CED-9 is only a substrate readout for active CED-3. Supporting Evidence: PMID:18776901 CED-9 was synthesized and labeled with 35S-methionine in the TNT Transcription/Translation coupled system |
| GO:0005515 protein binding | IPI PMID:21949250 A molecular switch that governs mitochondrial fusion and fis... | REMOVE | Summary: The DRP-1 interaction belongs to a debated mitochondrial-dynamics branch rather than core CED-9 apoptosis control. Reason: Physical interaction with DRP-1 may be relevant for non-core fission/fusion regulation, but generic protein binding is not an informative GO molecular function. Supporting Evidence: PMID:21949250 CED-9 also physically interacts with the mitochondrial fission protein DRP-1 |
| GO:0005515 protein binding | IPI PMID:9024666 Interaction between the C. elegans cell-death regulators CED... | MODIFY | Summary: CED-9 binds and sequesters CED-4, preventing apoptosome-mediated CED-3 activation until EGL-1 relieves the inhibition. Reason: The interaction with CED-4 is biologically a protein-sequestering activity: CED-9 holds the CED-4 dimer inactive and thereby blocks CED-4 oligomerization and CED-3 autoactivation. Generic protein binding should be narrowed to that activity. Proposed replacements: protein sequestering activity Supporting Evidence: PMID:9024666 Here we show that CED-9 interacts physically with CED-4. PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0005515 protein binding | IPI PMID:9027312 Interaction of CED-4 with CED-3 and CED-9: a molecular frame... | MODIFY | Summary: CED-9 binds and sequesters CED-4, preventing apoptosome-mediated CED-3 activation until EGL-1 relieves the inhibition. Reason: The interaction with CED-4 is biologically a protein-sequestering activity: CED-9 holds the CED-4 dimer inactive and thereby blocks CED-4 oligomerization and CED-3 autoactivation. Generic protein binding should be narrowed to that activity. Proposed replacements: protein sequestering activity Supporting Evidence: PMID:9027312 Here CED-9 and its mammalian homolog Bcl-xL (a member of the Bcl-2 family of cell death regulators) were both found to interact with and inhibit the function of CED-4. PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0005515 protein binding | IPI PMID:9027312 Interaction of CED-4 with CED-3 and CED-9: a molecular frame... | REMOVE | Summary: The CED-3 association is in a CED-4-containing complex context and is not a distinct CED-9 molecular function. Reason: CED-9 acts through CED-4 sequestration. The cached evidence does not establish a specific direct CED-9 activity toward CED-3 that should replace generic protein binding. Supporting Evidence: PMID:9027312 Here CED-9 and its mammalian homolog Bcl-xL (a member of the Bcl-2 family of cell death regulators) were both found to interact with and inhibit the function of CED-4. |
| GO:0005515 protein binding | IPI PMID:9027313 Interaction and regulation of subcellular localization of CE... | MODIFY | Summary: CED-9 binds and sequesters CED-4, preventing apoptosome-mediated CED-3 activation until EGL-1 relieves the inhibition. Reason: The interaction with CED-4 is biologically a protein-sequestering activity: CED-9 holds the CED-4 dimer inactive and thereby blocks CED-4 oligomerization and CED-3 autoactivation. Generic protein binding should be narrowed to that activity. Proposed replacements: protein sequestering activity Supporting Evidence: PMID:9027313 Expression of CED-9, but not a mutant lacking the carboxy-terminal hydrophobic domain, targeted CED-4 from the cytosol to intracellular membranes in mammalian cells. PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0005515 protein binding | IPI PMID:9261161 Interaction and regulation of the Caenorhabditis elegans dea... | MODIFY | Summary: CED-9 binds and sequesters CED-4, preventing apoptosome-mediated CED-3 activation until EGL-1 relieves the inhibition. Reason: The interaction with CED-4 is biologically a protein-sequestering activity: CED-9 holds the CED-4 dimer inactive and thereby blocks CED-4 oligomerization and CED-3 autoactivation. Generic protein binding should be narrowed to that activity. Proposed replacements: protein sequestering activity Supporting Evidence: PMID:9261161 Immunoprecipitation analysis demonstrates that CED-9 forms a multimeric protein complex with CED-4 and CED-3 in vivo. PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0005515 protein binding | IPI PMID:9261161 Interaction and regulation of the Caenorhabditis elegans dea... | REMOVE | Summary: The CED-3 association is in a CED-4-containing complex context and is not a distinct CED-9 molecular function. Reason: CED-9 acts through CED-4 sequestration. The cached evidence does not establish a specific direct CED-9 activity toward CED-3 that should replace generic protein binding. Supporting Evidence: PMID:9261161 CED-9 inhibits the formation of p13 and p15, two cleavage products of CED-3 associated with its proteolytic activation in vivo. |
| GO:0005515 protein binding | IPI PMID:9604928 The C. elegans protein EGL-1 is required for programmed cell... | MODIFY | Summary: The cited EGL-1 interaction is the BH3-only input that neutralizes CED-9 and releases CED-4. Reason: Replace generic protein binding with BH3 domain binding, the specific molecular recognition event by which CED-9 senses EGL-1 and changes conformation to release CED-4. Proposed replacements: BH3 domain binding Supporting Evidence: PMID:9604928 The EGL-1 and CED-9 proteins interact physically. 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. |
| GO:0005515 protein binding | IPI PMID:9742122 E1B 19,000-molecular-weight protein interacts with and inhib... | REMOVE | Summary: The adenoviral E1B 19K paper uses CED-9 as BCL2-family context while assaying viral E1B 19K inhibition of CED-4. Reason: The original experiment is about E1B 19K binding to CED-4 and inhibition of CED-4-dependent FLICE activation in mammalian cells, not a CED-9 function. Supporting Evidence: PMID:9742122 Thus, E1B 19K functions through interacting with CED-4, and presumably a mammalian homologue of CED-4, to inhibit caspase activation and apoptosis. |
| GO:0005515 protein binding | IPI PMID:9824163 Regulation of apoptosis by a Caenorhabditis elegans BNIP3 ho... | REMOVE | Summary: The ceBNIP3/DCT-1 interaction was detected in heterologous mammalian-cell experiments and does not define core CED-9 activity. Reason: The row is uninformative generic protein binding; the abstracts do not justify a specific direct CED-9 molecular function for DCT-1. Supporting Evidence: PMID:9824163 suggesting that CED-9 may suppress cooperative apoptosis induced by CED-3 and ceBNIP3 by simultaneous complex formation with CED-3 and ceBNIP3 |
| GO:0005737 cytoplasm | IDA PMID:17021039 Pax2/5/8 proteins promote cell survival in C. elegans. | UNDECIDED | Summary: The Pax2/5/8 abstract supports transcriptional regulation of ced-9 but does not expose the CED-9 cytoplasmic localization experiment. Reason: Because the cached paper is abstract-only and the abstract does not discuss CED-9 localization, defer this curator-visible IDA row to the full text. Supporting Evidence: PMID:17021039 we show that the Pax proteins act as transcriptional regulators of ced-9, the C. elegans bcl-2 gene |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: CED-9 is exposed to the cytoplasmic face of intracellular membranes including the mitochondrial outer membrane. Reason: The SubCell-derived cytoplasm row is broad but compatible with a CED-9 peripheral membrane protein on cytoplasmic faces of mitochondria and other intracellular membranes. Supporting Evidence: PMID:17703231 GFP:: CED-9 was localized at the outer surface of mitochondria |
| GO:0005739 mitochondrion | EXP PMID:10846174 Disruption of the CED-9.CED-4 complex by EGL-1 is a critical... | ACCEPT | Summary: Mitochondria are a core site of the CED-9/CED-4 resting complex. Reason: CED-9 is mitochondria-associated in the inhibited state where it holds CED-4 before EGL-1-dependent release. Supporting Evidence: PMID:10846174 CED-4 and CED-9G169E co-localizes with EGL-1 to the mitochondria in mammalian cells |
| GO:0005739 mitochondrion | IDA PMID:10688797 Translocation of C. elegans CED-4 to nuclear membranes durin... | ACCEPT | Summary: Mitochondria are a core site of the CED-9/CED-4 resting complex. Reason: CED-9 is mitochondria-associated in the inhibited state where it holds CED-4 before EGL-1-dependent release. Supporting Evidence: PMID:10688797 Endogenous CED-9 and CED-4 proteins localized to mitochondria in wild-type embryos |
| GO:0005739 mitochondrion | IDA PMID:12672828 A complex II defect affects mitochondrial structure, leading... | UNDECIDED | Summary: The mev-1 abstract reports altered CED-9 protein levels under hyperoxia but does not expose mitochondrial localization data. Reason: The cached abstract is insufficient for this IDA mitochondrion row, so defer to full-text WormBase curation. Supporting Evidence: PMID:12672828 show a loss of membrane potential, have altered CED-9 and Cyt-1 protein levels under hyperoxia |
| GO:0005741 mitochondrial outer membrane | IBA GO_REF:0000033 | ACCEPT | Summary: CED-9 localizes to the mitochondrial outer membrane through its C-terminal transmembrane domain. Reason: The outer-membrane localization is experimentally supported and phylogenetically consistent for the CED-9 subfamily. Supporting Evidence: PMID:17703231 GFP:: CED-9 was localized at the outer surface of mitochondria |
| GO:0005741 mitochondrial outer membrane | IDA PMID:17703231 Regulation of apoptosis by C. elegans CED-9 in the absence o... | ACCEPT | Summary: CED-9 localizes to the mitochondrial outer membrane through its C-terminal transmembrane domain. Reason: The outer-membrane localization is experimentally supported and phylogenetically consistent for the CED-9 subfamily. Supporting Evidence: PMID:17703231 GFP:: CED-9 was localized at the outer surface of mitochondria |
| GO:0006915 apoptotic process | IGI PMID:10101135 C. elegans MAC-1, an essential member of the AAA family of A... | MODIFY | Summary: The evidence concerns CED-9 as an anti-apoptotic brake, not the entire apoptotic process. Reason: CED-9 prevents CED-4/CED-3-driven apoptosis; a broad positive row to apoptotic process should be replaced by negative regulation of apoptotic process. Proposed replacements: negative regulation of apoptotic process Supporting Evidence: PMID:10101135 A MAC-1 transgene under the control of a heat shock promoter prevents some natural cell deaths in C. elegans, and this protection is enhanced in a ced-9(n1950sd)/+ genetic background. PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0006915 apoptotic process | IMP PMID:11226309 Programmed cell death mediated by ced-3 and ced-4 protects C... | MODIFY | Summary: The evidence concerns CED-9 as an anti-apoptotic brake, not the entire apoptotic process. Reason: CED-9 prevents CED-4/CED-3-driven apoptosis; a broad positive row to apoptotic process should be replaced by negative regulation of apoptotic process. Proposed replacements: negative regulation of apoptotic process Supporting Evidence: PMID:11226309 Table 1 shows that Salmonella -induced apoptosis is substantially reduced in the ced-9(n1950) mutant. PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage | IBA GO_REF:0000033 | MODIFY | Summary: The PAINT DNA-damage-specific row is too mammalian for CED-9. Reason: C. elegans CED-9 is an anti-apoptotic regulator of CED-4, but the mammalian intrinsic DNA-damage-to-MOMP branch should not be transferred wholesale to the worm pathway. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: LINEAGE OR TAXON MISMATCH GRANULARITY MISMATCH Sources checked: PANTHER:PTN000135648 · BCL-2-related family ancestral node SUPPORTS SOURCE BUT NOT TARGET The BCL2-family node mixes mammalian DNA-damage/MOMP wiring with nematode CED-4 sequestration. Proposed replacements: negative regulation of apoptotic process Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0010636 positive regulation of mitochondrial fusion | IMP PMID:18827010 CED-9 and mitochondrial homeostasis in C. elegans muscle. | KEEP AS NON CORE | Summary: CED-9 overexpression can affect the mitochondrial fission/fusion balance in muscle. Reason: This row captures a real reported mitochondrial-dynamics branch, but mitochondrial fusion/fission is not the central EGL-1/CED-9/CED-4/CED-3 apoptotic switch and the CED-9 dynamics literature is conflicting. Supporting Evidence: PMID:18827010 CED-9 is capable of regulating the mitochondrial fission-fusion cycle but is not essential for either fission or fusion. |
| GO:0012505 endomembrane system | EXP PMID:10688797 Translocation of C. elegans CED-4 to nuclear membranes durin... | ACCEPT | Summary: CED-9 is detected on intracellular membranes beyond a simple soluble cytosolic pool. Reason: Endomembrane is broad but consistent with the early CED-9 localization experiments and later ER-targeting rescue experiments. Supporting Evidence: PMID:9027313 The CED-9 protein localized primarily to intracellular membranes and the perinuclear region |
| GO:0012505 endomembrane system | EXP PMID:9027313 Interaction and regulation of subcellular localization of CE... | ACCEPT | Summary: CED-9 is detected on intracellular membranes beyond a simple soluble cytosolic pool. Reason: Endomembrane is broad but consistent with the early CED-9 localization experiments and later ER-targeting rescue experiments. Supporting Evidence: PMID:9027313 The CED-9 protein localized primarily to intracellular membranes and the perinuclear region |
| GO:0012505 endomembrane system | IEA GO_REF:0000044 | ACCEPT | Summary: CED-9 is detected on intracellular membranes beyond a simple soluble cytosolic pool. Reason: Endomembrane is broad but consistent with the early CED-9 localization experiments and later ER-targeting rescue experiments. Supporting Evidence: PMID:9027313 The CED-9 protein localized primarily to intracellular membranes and the perinuclear region |
| GO:0015267 channel activity | IBA GO_REF:0000033 | REMOVE | Summary: BCL2-family channel activity is not established for the CED-9 cell-death mechanism. Reason: This propagated molecular function is not supported by worm CED-9 data; CED-9 blocks apoptosis by sequestering CED-4 rather than by serving as a membrane channel. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE SOURCE EVIDENCE WEAK Sources checked: PANTHER:PTN000135648 · BCL-2-related family ancestral node SUPPORTS SOURCE BUT NOT TARGET The channel row is sourced only to mammalian BCL2-family members, with no CED-9 descendant evidence at PTN000135648. Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0016020 membrane | IDA PMID:9027313 Interaction and regulation of subcellular localization of CE... | MODIFY | Summary: The generic organelle-membrane localization should be represented by the better-supported mitochondrial outer membrane term. Reason: CED-9 is an intracellular membrane protein, but the specific direct location for its endogenous apoptotic role is the mitochondrial outer membrane. Proposed replacements: mitochondrial outer membrane Supporting Evidence: PMID:17703231 GFP:: CED-9 was localized at the outer surface of mitochondria |
| GO:0016485 protein processing | IDA PMID:18776901 Inhibition of CED-3 zymogen activation and apoptosis in Caen... | REMOVE | Summary: This row comes from a CSP caspase-homolog study; CED-9 is not the protein-processing factor. Reason: CED-9 prevents CED-4-dependent activation upstream of CED-3, whereas CSP-3 and CSP-2 are the caspase homologs assayed as direct inhibitors of CED-3 autoactivation in these papers. Supporting Evidence: PMID:18776901 CSP-3 associates with the large subunit of the CED-3 zymogen and inhibits zymogen autoactivation. |
| GO:0016485 protein processing | IDA PMID:19575016 Caenorhabditis elegans caspase homolog CSP-2 inhibits CED-3 ... | REMOVE | Summary: This row comes from a CSP caspase-homolog study; CED-9 is not the protein-processing factor. Reason: CED-9 prevents CED-4-dependent activation upstream of CED-3, whereas CSP-3 and CSP-2 are the caspase homologs assayed as direct inhibitors of CED-3 autoactivation in these papers. Supporting Evidence: PMID:19575016 CSP-2 associates with the CED-3 zymogen and inhibits its autoactivation |
| GO:0030042 actin filament depolymerization | IMP PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | MODIFY | Summary: CED-9 acts upstream in local CED-pathway synapse elimination, while CED-3 cleavage of GSNL-1 drives actin disassembly. Reason: Replace the direct actin depolymerization row with positive regulation of synapse pruning, the process affected by CED-9 gain of function in RME and DD neurons. Proposed replacements: positive regulation of synapse pruning Supporting Evidence: PMID:26074078 gain-of-function in the anti-apoptotic gene ced-9 induced elimination defects to a similar degree as ced-3(lf) mutants |
| GO:0031090 organelle membrane | IDA PMID:9027313 Interaction and regulation of subcellular localization of CE... | MODIFY | Summary: The generic organelle-membrane localization should be represented by the better-supported mitochondrial outer membrane term. Reason: CED-9 is an intracellular membrane protein, but the specific direct location for its endogenous apoptotic role is the mitochondrial outer membrane. Proposed replacements: mitochondrial outer membrane Supporting Evidence: PMID:17703231 GFP:: CED-9 was localized at the outer surface of mitochondria |
| GO:0031333 negative regulation of protein-containing complex assembly | IDA PMID:16208361 Structure of the CED-4-CED-9 complex provides insights into ... | ACCEPT | Summary: The CED-4/CED-9 structure shows CED-9 preventing CED-4 oligomerization into an active CED-3-activating apoptosome. Reason: CED-9 blocks the assembly transition of CED-4 by binding an asymmetric CED-4 dimer until EGL-1 induces CED-4 release. Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. 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. |
| GO:0031966 mitochondrial membrane | EXP PMID:10688797 Translocation of C. elegans CED-4 to nuclear membranes durin... | ACCEPT | Summary: CED-9 is a mitochondrial membrane protein in the resting CED-4-inhibited state. Reason: The mitochondrial membrane location is a direct component of the canonical CED-9/CED-4 complex before apoptosis. Supporting Evidence: PMID:10688797 Endogenous CED-9 and CED-4 proteins localized to mitochondria in wild-type embryos |
| GO:0031966 mitochondrial membrane | EXP PMID:9027313 Interaction and regulation of subcellular localization of CE... | ACCEPT | Summary: CED-9 is a mitochondrial membrane protein in the resting CED-4-inhibited state. Reason: The mitochondrial membrane location is a direct component of the canonical CED-9/CED-4 complex before apoptosis. Supporting Evidence: PMID:10688797 Endogenous CED-9 and CED-4 proteins localized to mitochondria in wild-type embryos |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | ACCEPT | Summary: CED-9 is a mitochondrial membrane protein in the resting CED-4-inhibited state. Reason: The mitochondrial membrane location is a direct component of the canonical CED-9/CED-4 complex before apoptosis. Supporting Evidence: PMID:10688797 Endogenous CED-9 and CED-4 proteins localized to mitochondria in wild-type embryos |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro-derived BCL2-family process row should carry CED-9's canonical inhibitory sign. Reason: CED-9 is a BCL2-family apoptosis regulator, but in the worm core pathway it negatively regulates apoptosis by sequestering CED-4. Proposed replacements: negative regulation of apoptotic process Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0043025 neuronal cell body | IDA PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | KEEP AS NON CORE | Summary: CED-9 localizes to the neuronal cell body in the synapse-elimination system. Reason: The RME/DD localization is experimentally observed for a nonlethal synapse-pruning use of the CED pathway rather than the whole-cell apoptosis core. Supporting Evidence: PMID:26074078 the axonal/synaptic localization of CED-9 and CED-3 depends on the presence of mitochondria in axons |
| GO:0043065 positive regulation of apoptotic process | EXP PMID:10846174 Disruption of the CED-9.CED-4 complex by EGL-1 is a critical... | MODIFY | Summary: The cited EGL-1 experiment establishes that EGL-1 relieves the inhibitory CED-9/CED-4 complex. Reason: For CED-9 itself, the direct role is negative regulation of apoptotic process; EGL-1 is the positive regulator that displaces CED-4 from CED-9. Proposed replacements: negative regulation of apoptotic process 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 | IBA GO_REF:0000033 | UNDECIDED | Summary: The BCL2-family PAINT node contains both positive and negative regulators, making the propagated positive row difficult to interpret for CED-9. Reason: CED-9 has context-dependent positive behavior reported in older literature, but the IBA row needs a PAINT node-level audit to distinguish CED-9-specific bifunctionality from family-wide regulatory-sign mixing. Propagation Review Root cause: UNRESOLVED Failure modes: REGULATORY SIGN INVERSION SOURCE EVIDENCE WEAK Sources checked: PANTHER:PTN000135648 · BCL-2-related family ancestral node SUPPORTS SOURCE BUT NOT TARGET Positive apoptosis regulation is placed at the same broad BCL2-family node as negative regulation. Supporting Evidence: PMID:9384385 Our results indicate that CED-9 prevents programmed cell death in C. elegans through two distinct mechanisms |
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | ACCEPT | Summary: CED-9 directly prevents activation of the CED-4/CED-3 apoptotic module. Reason: Negative regulation of apoptotic execution is the core CED-9 function: it binds CED-4, keeps CED-4 from activating CED-3, and is neutralized by EGL-1. Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. 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:0043066 negative regulation of apoptotic process | IGI PMID:11027303 Demonstration of the in vivo interaction of key cell death r... | ACCEPT | Summary: CED-9 directly prevents activation of the CED-4/CED-3 apoptotic module. Reason: Negative regulation of apoptotic execution is the core CED-9 function: it binds CED-4, keeps CED-4 from activating CED-3, and is neutralized by EGL-1. Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. 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:0043066 negative regulation of apoptotic process | IMP PMID:11027303 Demonstration of the in vivo interaction of key cell death r... | ACCEPT | Summary: CED-9 directly prevents activation of the CED-4/CED-3 apoptotic module. Reason: Negative regulation of apoptotic execution is the core CED-9 function: it binds CED-4, keeps CED-4 from activating CED-3, and is neutralized by EGL-1. Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. 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:0043069 negative regulation of programmed cell death | IMP PMID:9384385 Caenorhabditis elegans CED-9 protein is a bifunctional cell-... | ACCEPT | Summary: CED-9 directly prevents activation of the CED-4/CED-3 apoptotic module. Reason: Negative regulation of apoptotic execution is the core CED-9 function: it binds CED-4, keeps CED-4 from activating CED-3, and is neutralized by EGL-1. Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. 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:0043204 perikaryon | EXP PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | KEEP AS NON CORE | Summary: CED-9 localizes to neuronal and synaptic compartments during developmental synapse elimination. Reason: This localization supports a real local, nonlethal reuse of the CED pathway in pruning presynaptic material, but it is not the core apoptotic cell-death role. Supporting Evidence: PMID:26074078 the axonal/synaptic localization of CED-9 and CED-3 depends on the presence of mitochondria in axons |
| GO:0043204 perikaryon | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: CED-9 localizes to neuronal and synaptic compartments during developmental synapse elimination. Reason: This localization supports a real local, nonlethal reuse of the CED pathway in pruning presynaptic material, but it is not the core apoptotic cell-death role. Supporting Evidence: PMID:26074078 the axonal/synaptic localization of CED-9 and CED-3 depends on the presence of mitochondria in axons |
| GO:0045202 synapse | EXP PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | KEEP AS NON CORE | Summary: CED-9 localizes to neuronal and synaptic compartments during developmental synapse elimination. Reason: This localization supports a real local, nonlethal reuse of the CED pathway in pruning presynaptic material, but it is not the core apoptotic cell-death role. Supporting Evidence: PMID:26074078 the axonal/synaptic localization of CED-9 and CED-3 depends on the presence of mitochondria in axons |
| GO:0045202 synapse | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: CED-9 localizes to neuronal and synaptic compartments during developmental synapse elimination. Reason: This localization supports a real local, nonlethal reuse of the CED pathway in pruning presynaptic material, but it is not the core apoptotic cell-death role. Supporting Evidence: PMID:26074078 the axonal/synaptic localization of CED-9 and CED-3 depends on the presence of mitochondria in axons |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:9027313 Interaction and regulation of subcellular localization of CE... | ACCEPT | Summary: CED-9 was observed at intracellular membranes and the perinuclear region in early localization assays. Reason: The row is broader and more heterologous than endogenous mitochondrial localization, but it is directly supported by the cited CED-9/CED-4 cell-localization paper. Supporting Evidence: PMID:9027313 The CED-9 protein localized primarily to intracellular membranes and the perinuclear region |
| GO:0050807 regulation of synapse organization | IGI PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | MODIFY | Summary: The 26074078 phenotype is specifically failed elimination of transient presynaptic material. Reason: Replace generic regulation of synapse organization with positive regulation of synapse pruning, matching the CED-pathway role in eliminating RME and DD presynaptic components. Proposed replacements: positive regulation of synapse pruning Supporting Evidence: PMID:26074078 activation of the apoptosis pathway promotes GSNL-1 activation through cleavage at the C-terminal conserved site |
| 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 organismal endpoint of germline apoptosis perturbation. Reason: CED-9 affects Salmonella-induced germline apoptosis through the core death pathway, but defense against Gram-negative bacteria is an indirect host-fitness phenotype rather than work performed by CED-9. Supporting Evidence: PMID:11226309 both the ced-9(n1950) and the egl-1(n1084n3082) mutants were more susceptible to Salmonella -mediated killing |
| GO:0055085 transmembrane transport | IEA GO_REF:0000108 | REMOVE | Summary: The transmembrane-transport row is derived from unsupported propagated channel activity. Reason: Because the CED-9 channel-activity inference is not supported, the logical transmembrane-transport child inferred from it should also be removed. Propagation Review Root cause: PROPAGATION BAD Failure modes: SOURCE EVIDENCE WEAK Sources checked: GO:0015267 · channel activity SOURCE WEAK OR INFERRED The upstream IBA channel-activity row is unsupported for worm CED-9. Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0097192 extrinsic apoptotic signaling pathway in absence of ligand | IBA GO_REF:0000033 | REMOVE | Summary: Ligandless extrinsic apoptotic signaling is a mammalian death-receptor/BCL2-family branch that does not fit nematode CED-9. Reason: The worm EGL-1/CED-9/CED-4/CED-3 pathway is not death-receptor signaling in the absence of ligand, so this PAINT row should not transfer to ced-9. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH Sources checked: PANTHER:PTN000135648 · BCL-2-related family ancestral node SUPPORTS SOURCE BUT NOT TARGET The source node contains mammalian death-receptor pathway assertions outside the nematode pathway context. Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. |
| GO:0098793 presynapse | IDA PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | KEEP AS NON CORE | Summary: CED-9 localizes to neuronal and synaptic compartments during developmental synapse elimination. Reason: This localization supports a real local, nonlethal reuse of the CED pathway in pruning presynaptic material, but it is not the core apoptotic cell-death role. Supporting Evidence: PMID:26074078 the axonal/synaptic localization of CED-9 and CED-3 depends on the presence of mitochondria in axons |
| GO:0140311 protein sequestering activity | IDA PMID:16208361 Structure of the CED-4-CED-9 complex provides insights into ... | ACCEPT | Summary: CED-9 sequesters CED-4 in an inactive complex. Reason: Protein sequestering activity is the exact core molecular function shown by the CED-4/CED-9 crystal structure and reconstitution experiments. Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. 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. |
| GO:1900118 negative regulation of execution phase of apoptosis | IMP PMID:10101135 C. elegans MAC-1, an essential member of the AAA family of A... | ACCEPT | Summary: CED-9 directly prevents activation of the CED-4/CED-3 apoptotic module. Reason: Negative regulation of apoptotic execution is the core CED-9 function: it binds CED-4, keeps CED-4 from activating CED-3, and is neutralized by EGL-1. Supporting Evidence: PMID:16208361 This specific interaction prevents CED-4 from activating CED-3. 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:1902742 apoptotic process involved in development | IMP PMID:22801495 Programmed elimination of cells by caspase-independent cell ... | MARK AS OVER ANNOTATED | Summary: The PIG-1 cell-extrusion paper uses ced-9(gf) as a background that blocks canonical apoptosis. Reason: CED-9 is relevant as a way to reveal caspase-independent shedding when canonical apoptosis is blocked, but PIG-1 and PAR-4 execute the shedding mechanism. 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:1905808 positive regulation of synapse pruning | IGI PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | KEEP AS NON CORE | Summary: CED-9 acts in the local CED pathway that eliminates transient presynaptic components in RME and DD neurons. Reason: Positive regulation of synapse pruning is directly supported, but it is a specialized nonlethal reuse of the apoptosis module rather than the core whole-cell death function. 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. |
| GO:1905808 positive regulation of synapse pruning | IMP PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | KEEP AS NON CORE | Summary: CED-9 acts in the local CED pathway that eliminates transient presynaptic components in RME and DD neurons. Reason: Positive regulation of synapse pruning is directly supported, but it is a specialized nonlethal reuse of the apoptosis module rather than the core whole-cell death function. 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. |
Loading supporting content…
Download this section (compressed HTML)Q: Should CED-9 involvement in mitochondrial fission and fusion be modeled as a conserved BCL2-family activity or kept as a C. elegans context-specific branch until the conflicting mitochondrial-dynamics studies are reconciled?
Q: Should the positive-regulation-of-apoptosis PAINT assertion at PTN000135648 be split below the CED-9 subfamily, or is CED-9 bifunctionality sufficient to keep a conservative positive-regulation row?
Q: Is a more specific GO molecular function needed for anti-apoptotic sequestration of apoptosome adaptors, or is generic protein sequestering activity adequate for CED-9 and BCL2-family curation?
Experiment: Use endogenous ced-9 rescue alleles that independently disrupt the CED-4 interface, the EGL-1 BH3-binding groove, the C-terminal membrane anchor, and the reported DRP-1/FZO-1 interfaces, then quantify embryonic cell survival, CED-4 localization, CED-3 activation, and mitochondrial morphology in the same animals.
Hypothesis: CED-4 sequestration, rather than a separate channel or mitochondrial-dynamics activity, is sufficient for the essential CED-9 anti-apoptotic function.
Type: structure-guided endogenous rescue epistasis
Experiment: Image endogenously tagged CED-9, CED-4, EGL-1, CED-3, and GSNL-1 during RME and DD synapse pruning in BH3-groove and CED-4-interface ced-9 mutants to test whether the local pruning pathway requires the canonical inhibitory complex.
Hypothesis: Synaptic CED-9 uses the same CED-4-sequestering and EGL-1-release mechanism as whole-cell apoptosis but is spatially limited by axonal mitochondria.
Type: live imaging with separation-of-function mutants
ced-9 encodes the sole C. elegans homolog of the mammalian cell-death inhibitor Bcl-2; during development, ced-9 activity is essential for preventing cells from undergoing programmed cell death; ced-9 also appears to have proapoptotic activity; CED-9 functions by binding and repressing the activity of CED-4, a protein similar to human APAF-1 and positive regulator of CED-3 caspase activity; CED-9 localizes to the mitochondrial outer membrane, although this localization is not essential for CED-9 to regulate apoptosis.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)