CED-4 is the Caenorhabditis elegans Apaf-1-like apoptosome adaptor that links EGL-1/CED-9 mitochondrial apoptotic signaling to activation of the CED-3 caspase. In surviving cells, CED-4 dimers are held by CED-9 at mitochondria; after CED-9 inhibition, ATP/Mg-bound CED-4 oligomerizes into an octameric apoptosome that binds CED-3 zymogens and stimulates their autocatalytic maturation. CED-4 also moves to the nuclear envelope during apoptosis and is reused in selected nonlethal CED-pathway outputs, including developmental synapse elimination and cell-size control.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IDA PMID:16208361 Structure of the CED-4-CED-9 complex provides insights into ... | ACCEPT | Summary: Mg binding is consistent with the Mg/ATP-bound CED-4 nucleotide-binding fold observed in CED-4 structural studies. Reason: ATP/Mg binding is part of the Apaf-1-like nucleotide-binding module used in CED-4 apoptosome assembly. Supporting Evidence: PMID:11779177 CED-4 exhibited a marked preference for ATP over dATP in filter binding studies and in competition experiments. |
| 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 interaction is generic and inhibitory rather than CED-4's apoptosome activity. Reason: MAC-1 was found as a CED-4-binding anti-apoptotic factor; the binding row is not the core CED-4 molecular function. Supporting Evidence: PMID:10101135 Immunoprecipitation studies confirm that MAC-1 interacts with CED-4, and also with Apaf-1, the mammalian homologue of CED-4. |
| GO:0005515 protein binding | IPI PMID:10764728 The Caenorhabditis elegans sex determination protein FEM-1 i... | REMOVE | Summary: The FEM-1 interaction was shown in mammalian cells and does not define the core CED-4 activity. Reason: The CED-4/FEM-1 association is a heterologous interaction around a CED-3 substrate; it is too generic for CED-4 function. Supporting Evidence: PMID:10764728 Furthermore, CED-4 associates with FEM-1 in vitro and in vivo in mammalian cells and potentiates FEM-1-mediated apoptosis. |
| GO:0005515 protein binding | IPI PMID:10846174 Disruption of the CED-9.CED-4 complex by EGL-1 is a critical... | REMOVE | Summary: CED-9 binds and sequesters CED-4, but generic protein binding is not an informative CED-4 molecular function. Reason: The CED-9/CED-4 interaction is central to apoptosis control, yet the row only asserts undifferentiated protein binding. No more precise CED-9-binding GO term is available here, so the mechanistic CED-4 annotations capture the function. Supporting Evidence: PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. |
| GO:0005515 protein binding | IPI PMID:11027303 Demonstration of the in vivo interaction of key cell death r... | REMOVE | Summary: EGL-1 releases CED-4 indirectly through direct binding to CED-9. Reason: The EGL-1 studies support EGL-1/CED-9 binding and allosteric release of CED-4 from CED-9, not a specific CED-4 molecular function toward EGL-1. 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:0005515 protein binding | IPI PMID:14555965 Mutational analysis of the interacting cell death regulators... | REMOVE | Summary: EGL-1 releases CED-4 indirectly through direct binding to CED-9. Reason: The EGL-1 studies support EGL-1/CED-9 binding and allosteric release of CED-4 from CED-9, not a specific CED-4 molecular function toward EGL-1. 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:0005515 protein binding | IPI PMID:16208361 Structure of the CED-4-CED-9 complex provides insights into ... | REMOVE | Summary: CED-9 binds and sequesters CED-4, but generic protein binding is not an informative CED-4 molecular function. Reason: The CED-9/CED-4 interaction is central to apoptosis control, yet the row only asserts undifferentiated protein binding. No more precise CED-9-binding GO term is available here, so the mechanistic CED-4 annotations capture the function. Supporting Evidence: PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. |
| GO:0005515 protein binding | IPI PMID:16938876 Matefin/SUN-1 is a nuclear envelope receptor for CED-4 durin... | MODIFY | Summary: CED-4 binds the CED-3 caspase zymogen as part of apoptosome-mediated CED-3 activation. Reason: Use caspase binding rather than the uninformative protein-binding parent for the CED-4/CED-3 interaction. Proposed replacements: caspase binding Supporting Evidence: PMID:9109415 CED-4 was found to interact with CED-3. PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0005515 protein binding | IPI PMID:16938876 Matefin/SUN-1 is a nuclear envelope receptor for CED-4 durin... | REMOVE | Summary: SUN-1 binds CED-4 to recruit it to the nuclear envelope, but the row is an uninformative binding parent. Reason: SUN-1 binding is better captured as the mechanism behind CED-4 nuclear-envelope translocation rather than as generic protein binding on CED-4. Supporting Evidence: PMID:16938876 Our data demonstrate that matefin/SUN-1 binds CED-4 and is specifically required for CED-4 translocation and maintenance at the NE. |
| GO:0005515 protein binding | IPI PMID:9024666 Interaction between the C. elegans cell-death regulators CED... | REMOVE | Summary: CED-9 binds and sequesters CED-4, but generic protein binding is not an informative CED-4 molecular function. Reason: The CED-9/CED-4 interaction is central to apoptosis control, yet the row only asserts undifferentiated protein binding. No more precise CED-9-binding GO term is available here, so the mechanistic CED-4 annotations capture the function. Supporting Evidence: PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. |
| GO:0005515 protein binding | IPI PMID:9027313 Interaction and regulation of subcellular localization of CE... | REMOVE | Summary: CED-9 binds and sequesters CED-4, but generic protein binding is not an informative CED-4 molecular function. Reason: The CED-9/CED-4 interaction is central to apoptosis control, yet the row only asserts undifferentiated protein binding. No more precise CED-9-binding GO term is available here, so the mechanistic CED-4 annotations capture the function. Supporting Evidence: PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. |
| GO:0005515 protein binding | IPI PMID:9109415 Direct physical interaction between the Caenorhabditis elega... | MODIFY | Summary: CED-4 binds the CED-3 caspase zymogen as part of apoptosome-mediated CED-3 activation. Reason: Use caspase binding rather than the uninformative protein-binding parent for the CED-4/CED-3 interaction. Proposed replacements: caspase binding Supporting Evidence: PMID:9109415 CED-4 was found to interact with CED-3. PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0005515 protein binding | IPI PMID:9261161 Interaction and regulation of the Caenorhabditis elegans dea... | REMOVE | Summary: CED-9 binds and sequesters CED-4, but generic protein binding is not an informative CED-4 molecular function. Reason: The CED-9/CED-4 interaction is central to apoptosis control, yet the row only asserts undifferentiated protein binding. No more precise CED-9-binding GO term is available here, so the mechanistic CED-4 annotations capture the function. Supporting Evidence: PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. |
| GO:0005515 protein binding | IPI PMID:9261161 Interaction and regulation of the Caenorhabditis elegans dea... | MODIFY | Summary: CED-4 binds the CED-3 caspase zymogen as part of apoptosome-mediated CED-3 activation. Reason: Use caspase binding rather than the uninformative protein-binding parent for the CED-4/CED-3 interaction. Proposed replacements: caspase binding Supporting Evidence: PMID:9109415 CED-4 was found to interact with CED-3. PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0005515 protein binding | IPI PMID:9651369 The death inhibitory molecules CED-9 and CED-4L use a common... | MODIFY | Summary: CED-4 binds the CED-3 caspase zymogen as part of apoptosome-mediated CED-3 activation. Reason: Use caspase binding rather than the uninformative protein-binding parent for the CED-4/CED-3 interaction. Proposed replacements: caspase binding Supporting Evidence: PMID:9109415 CED-4 was found to interact with CED-3. PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0005515 protein binding | IPI PMID:9742122 E1B 19,000-molecular-weight protein interacts with and inhib... | REMOVE | Summary: The adenoviral E1B 19K interaction is a non-core xenologous viral inhibition assay and the specific BH-domain rows already capture the mapped interaction. Reason: This generic protein-binding row duplicates the more specific viral BH1/BH3-domain binding annotations from the same paper. Supporting Evidence: PMID:9742122 Thus, BH3 serves as the only E1B 19K binding site for Bax whereas CED-4 interacts independently with two regions of E1B 19K: BH3 and the central conserved region. |
| GO:0005515 protein binding | IPI PMID:9742122 E1B 19,000-molecular-weight protein interacts with and inhib... | REMOVE | Summary: The E1B 19K/EGL-1 paper does not establish a specific CED-4 function toward the listed worm interactor. Reason: The useful CED-4 evidence in this viral paper is its artificial FLICE activation and E1B 19K binding, not a new CED-4 protein-binding activity for the CED pathway. |
| GO:0005524 ATP binding | IDA PMID:11779177 Subcellular localization, oligomerization, and ATP-binding o... | ACCEPT | Summary: CED-4 binds ATP directly. Reason: Direct ATP-binding experiments showed an ATP preference by CED-4, consistent with its AAA+/NB-ARC-like apoptosome fold. Supporting Evidence: PMID:11779177 CED-4 exhibited a marked preference for ATP over dATP in filter binding studies and in competition experiments. |
| GO:0005524 ATP binding | IDA PMID:16208361 Structure of the CED-4-CED-9 complex provides insights into ... | ACCEPT | Summary: ATP binding is part of the CED-4 apoptosome nucleotide-binding fold. Reason: The CED-4/CED-9 structure and reconstitution work support the ATP-bound CED-4 scaffold used to activate CED-3. Supporting Evidence: PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. |
| GO:0005524 ATP binding | IDA PMID:9285582 Role of CED-4 in the activation of CED-3. | ACCEPT | Summary: ATP binding is a real CED-4 molecular function. Reason: Although this early structural letter is abstract-only in the cache, ATP binding is directly supported by later biochemical and structural work. Supporting Evidence: PMID:11779177 CED-4 exhibited a marked preference for ATP over dATP in filter binding studies and in competition experiments. |
| GO:0005634 nucleus | IDA PMID:10688797 Translocation of C. elegans CED-4 to nuclear membranes durin... | MODIFY | Summary: The nucleus row is better represented as CED-4 localization to nuclear membranes during apoptosis. Reason: Endogenous CED-4 moves from mitochondria to a perinuclear/nuclear-membrane compartment in cells induced to die; nuclear membrane is more specific than nucleus. Proposed replacements: nuclear membrane Supporting Evidence: PMID:10688797 By contrast, in embryos in which cells had been induced to die, CED-4 assumed a perinuclear localization. |
| GO:0005739 mitochondrion | EXP PMID:10846174 Disruption of the CED-9.CED-4 complex by EGL-1 is a critical... | ACCEPT | Summary: CED-4 is held at mitochondria by CED-9 in non-dying cells. Reason: Release of mitochondria-associated CED-4 from CED-9 is the proximal step that permits apoptotic signaling. Supporting Evidence: PMID:10846174 These studies suggest that 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. PMID:10688797 Endogenous CED-9 and CED-4 proteins localized to mitochondria in wild-type embryos, in which most cells survive. |
| GO:0005739 mitochondrion | EXP PMID:9027313 Interaction and regulation of subcellular localization of CE... | ACCEPT | Summary: CED-9 can target CED-4 to intracellular membranes and later in vivo work placed the endogenous complex at mitochondria. Reason: The row is consistent with CED-9-mediated mitochondrial sequestration of CED-4 before apoptosis. 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:10688797 Endogenous CED-9 and CED-4 proteins localized to mitochondria in wild-type embryos, in which most cells survive. |
| GO:0005739 mitochondrion | IDA PMID:10688797 Translocation of C. elegans CED-4 to nuclear membranes durin... | ACCEPT | Summary: Endogenous CED-4 localizes with CED-9 at mitochondria in wild-type embryos. Reason: Mitochondrial sequestration by CED-9 is a core regulatory localization for CED-4. Supporting Evidence: PMID:10688797 Endogenous CED-9 and CED-4 proteins localized to mitochondria in wild-type embryos, in which most cells survive. |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt SubCell mitochondrial mapping is consistent with endogenous CED-4 localization. Reason: Direct embryo staining showed endogenous CED-4 and CED-9 at mitochondria in surviving cells. Supporting Evidence: PMID:10688797 Endogenous CED-9 and CED-4 proteins localized to mitochondria in wild-type embryos, in which most cells survive. |
| GO:0005829 cytosol | IDA PMID:9027313 Interaction and regulation of subcellular localization of CE... | ACCEPT | Summary: Cytosolic CED-4 is observed when not sequestered to membranes. Reason: CED-4 is a soluble apoptosome subunit that was cytosolic without CED-9 in the original localization assays. 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. |
| GO:0005829 cytosol | IDA PMID:9742122 E1B 19,000-molecular-weight protein interacts with and inhib... | ACCEPT | Summary: Heterologously expressed CED-4 can be cytosolic/perinuclear and soluble. Reason: The E1B 19K study used a heterologous context, but a cytosolic pool is compatible with the soluble CED-4 adaptor released from CED-9. Supporting Evidence: PMID:9742122 E1B 19K expression altered the cytosolic localization of CED-4 to that of its own perinuclear membrane localization pattern. |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: The ARBA cytosol call is compatible with CED-4 being a soluble apoptosome adaptor. Reason: CED-4 is released from membrane-associated CED-9 to form a soluble apoptosome that activates CED-3. Supporting Evidence: PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. |
| GO:0006915 apoptotic process | IEA GO_REF:0000117 | MODIFY | Summary: The ARBA row should be narrowed from top-level apoptosis to the CED-4 apoptotic-signaling step. Reason: CED-4 does not execute apoptosis directly; it mediates upstream CED-3 activation in the worm apoptosome. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00027755 SUPPORTS TRANSFER ARBA inferred apoptosis for an Apaf-1-like protein; the specific CED-4 process is apoptotic signaling. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0006915 apoptotic process | IGI PMID:10101135 C. elegans MAC-1, an essential member of the AAA family of A... | MODIFY | Summary: CED-4 acts in the apoptotic signaling step that activates the CED-3 zymogen. Reason: CED-4 is upstream of execution: EGL-1/CED-9 control releases CED-4, and the CED-4 apoptosome then activates CED-3. Apoptotic signaling pathway is more precise than the top-level apoptotic process term. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. |
| GO:0006915 apoptotic process | IMP PMID:11226309 Programmed cell death mediated by ced-3 and ced-4 protects C... | MODIFY | Summary: CED-4 acts in the apoptotic signaling step that activates the CED-3 zymogen. Reason: CED-4 is upstream of execution: EGL-1/CED-9 control releases CED-4, and the CED-4 apoptosome then activates CED-3. Apoptotic signaling pathway is more precise than the top-level apoptotic process term. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. |
| GO:0006915 apoptotic process | IMP PMID:1286611 The Caenorhabditis elegans cell death gene ced-4 encodes a n... | MODIFY | Summary: CED-4 acts in the apoptotic signaling step that activates the CED-3 zymogen. Reason: CED-4 is upstream of execution: EGL-1/CED-9 control releases CED-4, and the CED-4 apoptosome then activates CED-3. Apoptotic signaling pathway is more precise than the top-level apoptotic process term. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. |
| GO:0006915 apoptotic process | IMP PMID:27723735 Regulation of CED-3 caspase localization and activation by C... | MODIFY | Summary: CED-4 acts in the apoptotic signaling step that activates the CED-3 zymogen. Reason: CED-4 is upstream of execution: EGL-1/CED-9 control releases CED-4, and the CED-4 apoptosome then activates CED-3. Apoptotic signaling pathway is more precise than the top-level apoptotic process term. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. |
| GO:0008303 caspase complex | IDA PMID:10101135 C. elegans MAC-1, an essential member of the AAA family of A... | ACCEPT | Summary: CED-4 is a subunit of the CED-4/CED-3 apoptosome caspase complex. Reason: Structural studies show the CED-4 apoptosome bound to CED-3 during caspase activation. Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0008303 caspase complex | IDA PMID:24065769 Mechanistic insights into CED-4-mediated activation of CED-3... | ACCEPT | Summary: CED-4 is a subunit of the CED-4/CED-3 apoptosome caspase complex. Reason: Structural studies show the CED-4 apoptosome bound to CED-3 during caspase activation. Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0008303 caspase complex | IMP PMID:24065769 Mechanistic insights into CED-4-mediated activation of CED-3... | ACCEPT | Summary: CED-4 is a subunit of the CED-4/CED-3 apoptosome caspase complex. Reason: Genetic loss of CED-4 disrupts the CED-4/CED-3 holoenzyme, and structural work directly supports the complex. Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0008361 regulation of cell size | IGI PMID:18635357 ced-4 and proto-oncogene tfg-1 antagonistically regulate cel... | KEEP AS NON CORE | Summary: CED-4 has a non-apoptotic role in limiting cell size. Reason: The TFG-1 study shows CED-4-dependent cell-size effects independent of caspases; keep this as a non-core output distinct from apoptosome-mediated apoptosis. Supporting Evidence: PMID:18635357 In summary, our findings on the function of the proto-oncogene TFG-1 and the pro-apoptotic factor CED-4 in apoptosis and cell size regulation suggest a possible link between these two key cellular processes |
| GO:0008656 cysteine-type endopeptidase activator activity involved in apoptotic process | IMP PMID:24065769 Mechanistic insights into CED-4-mediated activation of CED-3... | MODIFY | Summary: CED-4 enables apoptotic cysteine-type endopeptidase activator activity. Reason: The CED-4 apoptosome binds CED-3 and stimulates its autocatalytic maturation. Proposed replacements: cysteine-type endopeptidase activator activity Context of precomposed term: module c_elegans_core_apoptosis / ced4_caspase_activator in core functions Decomposed from the precomposed GO:0008656 (projects/INVOLVED_IN_PRECOMPOSITION.md) to its genus GO:0140608; the claim is unchanged and the apoptotic context is carried by the module c_elegans_core_apoptosis#ced4_caspase_activator and this review's core functions. Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. PMID:20434985 The CED-4 homo-oligomer or apoptosome is required for initiation of programmed cell death in Caenorhabditis elegans by facilitating autocatalytic activation of the CED-3 caspase zymogen. |
| GO:0009792 embryo development ending in birth or egg hatching | IGI PMID:21502138 Shared developmental roles and transcriptional control of au... | UNDECIDED | Summary: The autophagy/apoptosis genetic interaction is too distal for a confident ced-4 embryogenesis annotation from cached evidence. Reason: The cached abstract concerns ATF-2-dependent transcriptional control of autophagy and apoptosis; leave the exact broad embryo-development process to full-text worm curation. |
| GO:0009792 embryo development ending in birth or egg hatching | IGI PMID:21502138 Shared developmental roles and transcriptional control of au... | UNDECIDED | Summary: The autophagy/apoptosis genetic interaction is too distal for a confident ced-4 embryogenesis annotation from cached evidence. Reason: The cached abstract concerns ATF-2-dependent transcriptional control of autophagy and apoptosis; leave the exact broad embryo-development process to full-text worm curation. |
| GO:0009792 embryo development ending in birth or egg hatching | IGI PMID:21502138 Shared developmental roles and transcriptional control of au... | UNDECIDED | Summary: The autophagy/apoptosis genetic interaction is too distal for a confident ced-4 embryogenesis annotation from cached evidence. Reason: The cached abstract concerns ATF-2-dependent transcriptional control of autophagy and apoptosis; leave the exact broad embryo-development process to full-text worm curation. |
| GO:0010954 positive regulation of protein processing | IDA PMID:16208361 Structure of the CED-4-CED-9 complex provides insights into ... | MODIFY | Summary: ced-4 directly activates cysteine-type endopeptidases (caspases); the row is modified to cysteine-type endopeptidase activator activity, with the apoptotic context carried by the module and core functions. Reason: The replacement is the genus rather than the precomposed GO:0008656 (projects/INVOLVED_IN_PRECOMPOSITION.md); the apoptotic context is carried by the module c_elegans_core_apoptosis#ced4_caspase_activator and the core functions. Earlier reasoning, retained for its evidence (its term id updated to the genus): The asserted protein-processing or generic peptidase-activator parent is correct in essence but should be narrowed to CED-4 activation of a cysteine-type endopeptidase during apoptosis. Proposed replacements: cysteine-type endopeptidase activator activity Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0010954 positive regulation of protein processing | IDA PMID:18776901 Inhibition of CED-3 zymogen activation and apoptosis in Caen... | MODIFY | Summary: ced-4 directly activates cysteine-type endopeptidases (caspases); the row is modified to cysteine-type endopeptidase activator activity, with the apoptotic context carried by the module and core functions. Reason: The replacement is the genus rather than the precomposed GO:0008656 (projects/INVOLVED_IN_PRECOMPOSITION.md); the apoptotic context is carried by the module c_elegans_core_apoptosis#ced4_caspase_activator and the core functions. Earlier reasoning, retained for its evidence (its term id updated to the genus): The asserted protein-processing or generic peptidase-activator parent is correct in essence but should be narrowed to CED-4 activation of a cysteine-type endopeptidase during apoptosis. Proposed replacements: cysteine-type endopeptidase activator activity Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0016020 membrane | IDA PMID:9027313 Interaction and regulation of subcellular localization of CE... | MODIFY | Summary: The broad membrane row should be narrowed to CED-9-dependent mitochondrial localization. Reason: CED-9 targets CED-4 to intracellular membranes, and endogenous CED-4/CED-9 localize to mitochondria in surviving embryos. Proposed replacements: mitochondrion 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:10688797 Endogenous CED-9 and CED-4 proteins localized to mitochondria in wild-type embryos, in which most cells survive. |
| GO:0016505 peptidase activator activity involved in apoptotic process | IDA PMID:9285582 Role of CED-4 in the activation of CED-3. | MODIFY | Summary: CED-4 is the apoptotic activator of the CED-3 cysteine-type endopeptidase. Reason: The source term combines a generic peptidase activator activity with an apoptotic context. CED-4 activates a cysteine-type endopeptidase (CED-3), so the activity is narrowed to cysteine-type endopeptidase activator activity, and the apoptotic context is carried by the module and core functions rather than by a precomposed term (see decomposed_into). Proposed replacements: cysteine-type endopeptidase activator activity Context of precomposed term: module c_elegans_core_apoptosis / ced4_caspase_activator in core functions Decomposed from the precomposed GO:0016505 (projects/INVOLVED_IN_PRECOMPOSITION.md) to its genus GO:0140608; the claim is unchanged and the apoptotic context is carried by the module c_elegans_core_apoptosis#ced4_caspase_activator and this review's core functions. The source term is itself precomposed (peptidase activator activity involved in apoptotic process); the earlier replacement GO:0008656 is replaced by its genus. Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0030042 actin filament depolymerization | IMP PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | MODIFY | Summary: CED-4 acts upstream of GSNL-1-dependent actin disassembly during synapse pruning. Reason: GSNL-1 is the actin-severing effector; CED-4 acts with the CED pathway to activate CED-3, so synapse pruning is the supported process. Proposed replacements: positive regulation of synapse pruning 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:0030155 regulation of cell adhesion | IMP PMID:22801495 Programmed elimination of cells by caspase-independent cell ... | MARK AS OVER ANNOTATED | Summary: The PIG-1 cell-adhesion phenotype is an endpoint of a shedding pathway rather than direct CED-4 work on adhesion. Reason: This pathway concerns caspase-independent extrusion of cells that would survive in ced-3 or ced-4 mutants, so regulation of cell adhesion is too downstream for CED-4. |
| GO:0031647 regulation of protein stability | IGI PMID:24285704 Maintenance of muscle myosin levels in adult C. elegans requ... | UNDECIDED | Summary: The adult muscle myosin phenotype needs full-text review before assigning a direct CED-4 protein-stability role. Reason: The study links bet-1/sumo-1-dependent muscle myosin maintenance to the caspase pathway, but the cached paper does not establish CED-4 as the direct regulator of myosin stability. |
| GO:0032991 protein-containing complex | IDA PMID:16208361 Structure of the CED-4-CED-9 complex provides insights into ... | TOO GENERAL | Summary: Protein-containing complex is too broad for the CED-4/CED-9 structure. Reason: The row only says CED-4 is in a complex; the functional complexes are represented by CED-9 sequestration and the CED-4/CED-3 caspase complex. TOO_GENERAL rather than REMOVE: caspase complex, kept in this review, entails this term, so the claim is true but less informative. |
| 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 study does not establish an exact heterochronic-development role for CED-4 from cached evidence. Reason: CED-3 directly cleaves heterochronic/miRNA regulators in this paper, but the CED-4 row needs full context before asserting this non-apoptotic developmental process. |
| GO:0042802 identical protein binding | IPI PMID:16208361 Structure of the CED-4-CED-9 complex provides insights into ... | ACCEPT | Summary: CED-4 self-association is required for apoptosome assembly. Reason: CED-4 forms an asymmetric dimer when held by CED-9 and then oligomerizes after release to form the active apoptosome. Supporting Evidence: PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. PMID:20434985 The CED-4 homo-oligomer or apoptosome is required for initiation of programmed cell death in Caenorhabditis elegans by facilitating autocatalytic activation of the CED-3 caspase zymogen. |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro2GO regulation row should be narrowed to CED-4 apoptotic signaling. Reason: The CARD-domain InterPro mapping captures an apoptotic adaptor module but lands one level too generically for CED-4. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR001315 SUPPORTS TRANSFER The domain source supports apoptosome signaling but not the broader regulation parent as the best CED-4 process. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| 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: CED-4 acts in the apoptotic signaling step that activates the CED-3 zymogen. Reason: CED-4 is upstream of execution: EGL-1/CED-9 control releases CED-4, and the CED-4 apoptosome then activates CED-3. Apoptotic signaling pathway is more precise than the top-level apoptotic process term. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. PMID:16208361 The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:9742122 E1B 19,000-molecular-weight protein interacts with and inhib... | MODIFY | Summary: ced-4 directly activates cysteine-type endopeptidases (caspases); the row is modified to cysteine-type endopeptidase activator activity, with the apoptotic context carried by the module and core functions. Reason: The replacement is the genus rather than the precomposed GO:0008656 (projects/INVOLVED_IN_PRECOMPOSITION.md); the apoptotic context is carried by the module c_elegans_core_apoptosis#ced4_caspase_activator and the core functions. Earlier reasoning, retained for its evidence (its term id updated to the genus): The asserted protein-processing or generic peptidase-activator parent is correct in essence but should be narrowed to CED-4 activation of a cysteine-type endopeptidase during apoptosis. Proposed replacements: cysteine-type endopeptidase activator activity Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:23431138 Related F-box proteins control cell death in Caenorhabditis ... | UNDECIDED | Summary: The DRE-1/CED-9 apoptosis paper does not establish the exact CED-4 assertion from cached evidence. Reason: The cached abstract places DRE-1 in parallel to EGL-1 and upstream of CED-9; leave the CED-4 positive-regulation row to full-text worm curation. 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:0043531 ADP binding | IEA GO_REF:0000002 | UNDECIDED | Summary: ADP binding is not established for the ATP-preferring CED-4 apoptosome from the cached evidence. Reason: InterPro2GO infers ADP binding from the NB-ARC-like nucleotide-binding domain, whereas the CED-4 biochemical evidence specifically shows ATP preference. Propagation Review Root cause: UNRESOLVED Failure modes: SOURCE EVIDENCE WEAK Sources checked: InterPro:IPR002182 UNRESOLVED The domain can justify nucleotide binding, but this CED-4 review only verified ATP preference, not a physiological ADP-bound state. Supporting Evidence: PMID:11779177 CED-4 exhibited a marked preference for ATP over dATP in filter binding studies and in competition experiments. |
| GO:0046716 muscle cell cellular homeostasis | IGI PMID:24285704 Maintenance of muscle myosin levels in adult C. elegans requ... | UNDECIDED | Summary: The adult muscle homeostasis row needs full-text review before assigning this indirect endpoint to CED-4. Reason: The cached muscle-myosin study is not enough to decide whether CED-4 itself executes a muscle-cell homeostasis function or only modifies the endpoint through caspase signaling. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:10688797 Translocation of C. elegans CED-4 to nuclear membranes durin... | ACCEPT | Summary: CED-4 moves to a perinuclear/nuclear-envelope compartment in cells induced to die. Reason: The endogenous localization study directly showed perinuclear CED-4 during apoptosis. Supporting Evidence: PMID:10688797 By contrast, in embryos in which cells had been induced to die, CED-4 assumed a perinuclear localization. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:18042457 Nonapoptotic role for Apaf-1 in the DNA damage checkpoint. | UNDECIDED | Summary: The cached Apaf-1 DNA-damage-checkpoint abstract does not verify perinuclear CED-4 localization. Reason: CED-4 has a non-apoptotic DNA-damage checkpoint connection, but the abstract-only cache does not show the exact localization experiment behind this row. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:9027313 Interaction and regulation of subcellular localization of CE... | ACCEPT | Summary: CED-9 can target CED-4 to the perinuclear region in cell localization assays. Reason: The original CED-9 localization work placed CED-4 at intracellular membranes/perinuclear regions when CED-9 is expressed. 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. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:9742122 E1B 19,000-molecular-weight protein interacts with and inhib... | KEEP AS NON CORE | Summary: The adenoviral E1B 19K study observed a perinuclear CED-4 relocalization in a heterologous assay. Reason: Keep this as a non-core heterologous localization row rather than a central C. elegans apoptosome localization. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt perinuclear mapping is consistent with apoptotic CED-4 movement to the nuclear envelope. Reason: Endogenous CED-4 assumes a perinuclear localization when cells are induced to die. Supporting Evidence: PMID:10688797 By contrast, in embryos in which cells had been induced to die, CED-4 assumed a perinuclear localization. |
| GO:0048598 embryonic morphogenesis | IGI PMID:21285529 Autophagy and apoptosis are redundantly required for C. eleg... | MARK AS OVER ANNOTATED | Summary: Embryonic morphogenesis is an over-specific endpoint of combined autophagy/apoptosis loss. Reason: The source describes severe morphogenesis defects only when both autophagy and apoptosis are removed, so embryonic morphogenesis overstates direct CED-4 apoptotic-signaling work. |
| 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 survival is a pathogen endpoint of germline apoptosis rather than CED-4-specific antibacterial activity. Reason: Salmonella-induced germline apoptosis depends on ced-3 and ced-4, but this does not show that CED-4 performs defense-response work specific to Gram-negative bacteria. |
| GO:0051432 BH1 domain binding | IPI PMID:9742122 E1B 19,000-molecular-weight protein interacts with and inhib... | KEEP AS NON CORE | Summary: Adenoviral E1B 19K BH1-region binding is a direct but viral, non-core CED-4 interaction. Reason: The paper maps an artificial viral inhibitor surface rather than a conserved C. elegans CED-4 function. Supporting Evidence: PMID:9742122 Thus, BH3 serves as the only E1B 19K binding site for Bax whereas CED-4 interacts independently with two regions of E1B 19K: BH3 and the central conserved region. |
| GO:0051434 BH3 domain binding | IPI PMID:9742122 E1B 19,000-molecular-weight protein interacts with and inhib... | KEEP AS NON CORE | Summary: Adenoviral E1B 19K BH3-region binding is a direct but viral, non-core CED-4 interaction. Reason: The paper maps an artificial viral inhibitor surface rather than a conserved C. elegans CED-4 function. Supporting Evidence: PMID:9742122 Thus, BH3 serves as the only E1B 19K binding site for Bax whereas CED-4 interacts independently with two regions of E1B 19K: BH3 and the central conserved region. |
| GO:0061133 endopeptidase activator activity | IDA PMID:16208361 Structure of the CED-4-CED-9 complex provides insights into ... | MODIFY | Summary: ced-4 directly activates cysteine-type endopeptidases (caspases); the row is modified to cysteine-type endopeptidase activator activity, with the apoptotic context carried by the module and core functions. Reason: The replacement is the genus rather than the precomposed GO:0008656 (projects/INVOLVED_IN_PRECOMPOSITION.md); the apoptotic context is carried by the module c_elegans_core_apoptosis#ced4_caspase_activator and the core functions. Earlier reasoning, retained for its evidence (its term id updated to the genus): The asserted protein-processing or generic peptidase-activator parent is correct in essence but should be narrowed to CED-4 activation of a cysteine-type endopeptidase during apoptosis. Proposed replacements: cysteine-type endopeptidase activator activity Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0089720 caspase binding | IPI PMID:24065769 Mechanistic insights into CED-4-mediated activation of CED-3... | ACCEPT | Summary: CED-4 binds the CED-3 caspase to form the activating apoptosome holoenzyme. Reason: Structural work directly demonstrated specific CED-3 recognition by the CED-4 apoptosome. Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0140608 cysteine-type endopeptidase activator activity | IDA PMID:18776901 Inhibition of CED-3 zymogen activation and apoptosis in Caen... | ACCEPT | Summary: ced-4 directly activates cysteine-type endopeptidases (caspases). The genus term is correct as it stands; the apoptotic context is carried by the module and core functions, not by a precomposed term. Reason: The genus GO:0140608 is the right term. An earlier pass proposed MODIFY to the precomposed GO:0008656; per projects/INVOLVED_IN_PRECOMPOSITION.md that adds only the apoptotic context, which is carried by the module c_elegans_core_apoptosis#ced4_caspase_activator and the core functions. Superseded reasoning (it argued for the precomposed term), retained only for its evidence: The asserted protein-processing or generic peptidase-activator parent is correct in essence but should be narrowed to CED-4 activation of a cysteine-type endopeptidase during apoptosis. Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0140608 cysteine-type endopeptidase activator activity | IDA PMID:19575016 Caenorhabditis elegans caspase homolog CSP-2 inhibits CED-3 ... | ACCEPT | Summary: ced-4 directly activates cysteine-type endopeptidases (caspases). The genus term is correct as it stands; the apoptotic context is carried by the module and core functions, not by a precomposed term. Reason: The genus GO:0140608 is the right term. An earlier pass proposed MODIFY to the precomposed GO:0008656; per projects/INVOLVED_IN_PRECOMPOSITION.md that adds only the apoptotic context, which is carried by the module c_elegans_core_apoptosis#ced4_caspase_activator and the core functions. Superseded reasoning (it argued for the precomposed term), retained only for its evidence: The asserted protein-processing or generic peptidase-activator parent is correct in essence but should be narrowed to CED-4 activation of a cysteine-type endopeptidase during apoptosis. Supporting Evidence: PMID:24065769 CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. |
| GO:0160108 animal gross anatomical part developmental process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: The electronic animal-development call is an over-broad endpoint for a CED-3 activator. Reason: CED-4 has direct apoptotic-signaling and caspase-activation roles; animal gross anatomical part developmental process is a downstream ARBA endpoint. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00098139 SUPPORTS TRANSFER ARBA propagated a developmental parent instead of the direct apoptotic-signaling process. |
| 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... | REMOVE | Summary: MAC-1 is the inhibitor in this pathway; CED-4 is not a negative regulator of apoptotic execution. Reason: CED-4 activates CED-3. The MAC-1 paper supports MAC-1 prevention of CED-4/CED-3-induced apoptosis, not negative regulation by CED-4. Supporting Evidence: PMID:10101135 Immunoprecipitation studies confirm that MAC-1 interacts with CED-4, and also with Apaf-1, the mammalian homologue of CED-4. |
| 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 should not annotate CED-4 to developmental apoptosis. Reason: The phenotype is an indirect endpoint of cells that survive canonical apoptosis and are removed by extrusion, rather than direct CED-4 participation in that extrusion pathway. |
| GO:1904747 positive regulation of apoptotic process involved in development | IGI PMID:23505386 Both the caspase CSP-1 and a caspase-independent pathway pro... | MODIFY | Summary: CED-4 remains the canonical CED-3 activation branch in the CSP-1 combinatorial genetics. Reason: The paper distinguishes CSP-1 and caspase-independent branches from the canonical CED-4/CED-3 pathway; apoptotic signaling pathway is the direct CED-4 process. Proposed replacements: apoptotic signaling pathway 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:1904747 positive regulation of apoptotic process involved in development | IGI PMID:23505386 Both the caspase CSP-1 and a caspase-independent pathway pro... | MODIFY | Summary: CED-4 remains the canonical CED-3 activation branch in the CSP-1 combinatorial genetics. Reason: The paper distinguishes CSP-1 and caspase-independent branches from the canonical CED-4/CED-3 pathway; apoptotic signaling pathway is the direct CED-4 process. Proposed replacements: apoptotic signaling pathway 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:1904747 positive regulation of apoptotic process involved in development | IMP PMID:23505386 Both the caspase CSP-1 and a caspase-independent pathway pro... | MODIFY | Summary: CED-4 remains the canonical CED-3 activation branch in the CSP-1 combinatorial genetics. Reason: The paper distinguishes CSP-1 and caspase-independent branches from the canonical CED-4/CED-3 pathway; apoptotic signaling pathway is the direct CED-4 process. Proposed replacements: apoptotic signaling pathway 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 | IGI PMID:26074078 The Cell Death Pathway Regulates Synapse Elimination through... | KEEP AS NON CORE | Summary: CED-4 promotes local, non-apoptotic synapse pruning through the CED pathway in RME neurons. Reason: The RME-neuron study directly requires ced-4 for elimination of transient presynaptic clusters, but this is a restricted nonlethal reuse of the apoptotic pathway. 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-4 promotes local, non-apoptotic synapse pruning through the CED pathway in RME neurons. Reason: The RME-neuron study directly requires ced-4 for elimination of transient presynaptic clusters, but this is a restricted nonlethal reuse of the apoptotic pathway. 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 C. elegans or metazoan apoptosome-assembly process term for CED-4/APAF1-like oligomerization that sits between apoptotic signaling and caspase zymogen activation?
Q: Should the non-apoptotic CED-4-dependent regulation of cell size be modeled as a separate pathway with an unknown effector, or left as a phenotype until the molecular output downstream of CED-4 is identified?
Q: How should local reuse of EGL-1, CED-9, CED-4, and CED-3 in developmental synapse pruning be represented without implying whole-cell apoptosis?
Experiment: Introduce CED-4 separation-of-function mutations that impair the CED-3 L2-loop interface or oligomerization into an endogenous ced-4 rescue transgene and score embryonic cell corpses, CED-3 processing, and RME presynaptic-cluster elimination in the same animals.
Hypothesis: CED-4 apoptosome assembly surfaces that recruit CED-3 are also required for the nonlethal synapse-pruning pathway.
Type: endogenous rescue with apoptosome-interface mutants
Experiment: Compare phosphoproteome and size phenotypes after acute TFG-1 depletion in wild-type, ced-4-null, ced-3-null, and catalytically inactive CED-3 rescue backgrounds to separate CED-4 scaffold activity from canonical caspase activation.
Hypothesis: CED-4-dependent cell-size control uses a caspase-independent effector distinct from CED-3.
Type: epistasis proteomics and cell-size assay
ced-4 encodes a novel protein; along with CED-3, CED-4 is required for the initiation of programmed cell death; accordingly, genetic analyses indicate that ced-3 and ced-4 function upstream of ced-1, ced-2, and nuc-1 in the programmed cell death pathway; in yeast two-hybrid experiments, and upon coexpression in mammalian cells, CED-4 interacts with CED-9, an anti-apoptotic BCL-2 homolog; coexpression of CED-4 and CED-9 results in redistribution of CED-4 from the cytosol to organellar membranes, suggesting that CED-9 may negatively regulate CED-4 activity by sequestering CED-4 to intracellular membranes.
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