CED-7 is a C. elegans ABCA-family ATP-binding cassette transporter, the orthologue of mammalian ABCA1. It has two homologous halves, each with a membrane-spanning domain and an ATP-binding cassette, and it localizes to the plasma membrane. It is broadly expressed in embryos, and mosaic analysis shows it acts in both dying and engulfing cells during corpse engulfment. CED-7 belongs to the CED-1/CED-6/CED-7 engulfment pathway. It is required for the CED-1 receptor to cluster around cell corpses and for actin reorganization around them. With the secreted phosphatidylserine (PS)-binding bridging protein TTR-52, it promotes the release of PS-containing extracellular vesicles from apoptotic cells. Those vesicles lead to PS exposure on neighbouring engulfing cells, which depends on CED-1 and helps corpse clearance. Like other engulfment genes, ced-7 helps engulfing cells promote the death of cells that receive weak death signals.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000132 establishment of mitotic spindle orientation | IGI PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | REMOVE | Summary: Establishment of mitotic spindle orientation (IGI with mom-5, Cabello et al. 2010). Reason: Full text read. The spindle orientation phenotypes in this paper depend on MOM-5/Frizzled, GSK-3, beta-catenins and CED-10. The authors state that apart from ced-10 none of the other ced genes showed a strong defect. ced-7 is not in the one genotype with rare defects (ced-1; ced-5 double mutants), so there is no positive evidence for ced-7 in this process; the paper's own statement contradicts it. Same action as for ced-6 and ced-12; ced-1 and ced-5, which are in that double mutant, are marked over-annotated instead. Supporting Evidence: PMID:20126385 neither apr-1 nor any of the other ced genes showed a strong defect, suggesting that the link to CED-10 may not occur through CED-2/5/12 as is the case for engulfment and DTC migration |
| GO:0005319 lipid carrier activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Lipid carrier activity, by phylogenetic inference from ABCA-family members. Reason: Lipid carrier activity is defined as directly binding a lipid and delivering it to an acceptor or location, which describes soluble lipid-transfer proteins. ABCA transporters move lipids across or out of the membrane by ATP-coupled transport, which the ATPase-coupled and ABC-type transporter terms already capture. For CED-7 there is genetic evidence for PS efflux but no data on lipid binding or delivery by the protein itself. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN000442469 · PTN000442469 UNRESOLVED ABCA node whose seeds are mammalian ABCA transporters. The question is whether lipid carrier activity (bind and deliver) fits ATP-driven lipid efflux by ABCA transporters at all; node placement for CED-7 is not disputed. Supporting Evidence: PMID:22727702 CED-7 and TTR-52 may promote the efflux of PS from apoptotic cells through the generation of extracellular PS vesicles |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ATP binding, from InterPro ABC transporter domain mappings. Reason: CED-7 has two ATP-binding cassettes, so ATP binding is correct from domain architecture. It is part of the transport mechanism rather than a separate function. Supporting Evidence: PMID:9635425 the CED-7 protein has sequence similarity to ABC transporters, is broadly expressed during embryogenesis, and is localized to the plasma membrane |
| GO:0005886 plasma membrane | IDA PMID:9635425 The C. elegans cell corpse engulfment gene ced-7 encodes a p... | ACCEPT | Summary: Plasma membrane (Wu and Horvitz 1998). Reason: CED-7 was localized to the plasma membrane. This is where it acts in both dying and engulfing cells. Supporting Evidence: PMID:9635425 the CED-7 protein has sequence similarity to ABC transporters, is broadly expressed during embryogenesis, and is localized to the plasma membrane |
| GO:0006869 lipid transport | IBA GO_REF:0000033 | ACCEPT | Summary: Lipid transport, by phylogenetic inference from ABCA-family members. Reason: Consistent with the family and with CED-7 genetic data: CED-7 is needed for PS efflux from apoptotic cells in extracellular vesicles. Supporting Evidence: PMID:22727702 CED-7 and TTR-52 may promote the efflux of PS from apoptotic cells through the generation of extracellular PS vesicles PMID:22727702 indicating that CED-7 and TTR-52 promote the generation of extracellular PS vesicles |
| GO:0006869 lipid transport | ISS PMID:9635425 The C. elegans cell corpse engulfment gene ced-7 encodes a p... | ACCEPT | Summary: Lipid transport, by similarity to mouse ABC1/ABCA1 (Wu and Horvitz 1998). Reason: The similarity transfer to ABCA1, a lipid efflux transporter, is supported by later CED-7 data on PS efflux. Supporting Evidence: PMID:9635425 Like CED-7, the mammalian ABC transporter ABC1 has been implicated in the engulfment of cell corpses PMID:22727702 CED-7 and TTR-52 may promote the efflux of PS from apoptotic cells through the generation of extracellular PS vesicles |
| GO:0012501 programmed cell death | IMP PMID:9635425 The C. elegans cell corpse engulfment gene ced-7 encodes a p... | MARK AS OVER ANNOTATED | Summary: Programmed cell death, from the ced-7 cloning paper (Wu and Horvitz 1998). Reason: The paper studies the engulfment of cell corpses; ced-7 mutants have persistent corpses, not altered death. The death-promoting role of engulfment genes is captured by the positive regulation term. Supporting Evidence: PMID:9635425 The C. elegans gene ced-7 functions in the engulfment of cell corpses during programmed cell death PMID:11449278 mutations in engulfment genes enhance the frequency of this cell survival |
| GO:0016020 membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Membrane, from InterPro and UniProt subcellular location. Reason: Correct but less specific than the experimentally supported plasma membrane annotation. Supporting Evidence: PMID:9635425 the CED-7 protein has sequence similarity to ABC transporters, is broadly expressed during embryogenesis, and is localized to the plasma membrane |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ATP hydrolysis activity, from InterPro ABC transporter domain mappings. Reason: Expected for an ABC transporter. It is the energy-coupling part of the ABC-type transporter activity, which is the core function. Supporting Evidence: PMID:9635425 the CED-7 protein has sequence similarity to ABC transporters, is broadly expressed during embryogenesis, and is localized to the plasma membrane |
| GO:0022857 transmembrane transporter activity | ISS PMID:9635425 The C. elegans cell corpse engulfment gene ced-7 encodes a p... | KEEP AS NON CORE | Summary: Transmembrane transporter activity, by similarity to ABC1/ABCA1 (Wu and Horvitz 1998). Reason: Correct but general. ABC-type transporter activity, also annotated, is the specific term. Supporting Evidence: PMID:9635425 the CED-7 protein has sequence similarity to ABC transporters, is broadly expressed during embryogenesis, and is localized to the plasma membrane PMID:9635425 Like CED-7, the mammalian ABC transporter ABC1 has been implicated in the engulfment of cell corpses |
| GO:0033700 phospholipid efflux | IMP PMID:22727702 CED-1, CED-7, and TTR-52 regulate surface phosphatidylserine... | ACCEPT | Summary: Phospholipid efflux; CED-7 is needed for loss of surface PS from apoptotic cells and for PS-containing extracellular vesicles (Mapes et al. 2012). Reason: Core process. In ced-7 mutants exposed PS persists on unengulfed corpses, extracellular PS vesicles are absent or reduced, and engulfing cells fail to acquire exposed PS. The authors conclude that CED-7 and TTR-52 promote PS efflux from apoptotic cells. Supporting Evidence: PMID:22727702 CED-7 and TTR-52 may promote the efflux of PS from apoptotic cells through the generation of extracellular PS vesicles PMID:22727702 indicating that CED-7 and TTR-52 promote the generation of extracellular PS vesicles PMID:22727702 Phagocytic cells also express exPS, which is dependent on the activity of CED-7, TTR-52, and TTR-52-interacting phagocyte receptor CED-1 |
| GO:0042626 ATPase-coupled transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: ATPase-coupled transmembrane transporter activity, by phylogenetic inference. Reason: CED-7 is a full-length ABCA transporter with two transmembrane domains and two ATP-binding cassettes. The family-level activity is well supported, although CED-7 transport has not been reconstituted biochemically. Supporting Evidence: PMID:9635425 the CED-7 protein has sequence similarity to ABC transporters, is broadly expressed during embryogenesis, and is localized to the plasma membrane |
| GO:0042626 ATPase-coupled transmembrane transporter activity | NAS PMID:9635425 The C. elegans cell corpse engulfment gene ced-7 encodes a p... | ACCEPT | Summary: ATPase-coupled transmembrane transporter activity, as stated in the cloning paper. Reason: Matches the sequence-based assignment and the IBA. Supporting Evidence: PMID:9635425 the CED-7 protein has sequence similarity to ABC transporters, is broadly expressed during embryogenesis, and is localized to the plasma membrane |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Transmembrane transport, from InterPro. Reason: Correct but general. Phospholipid efflux is the specific supported process. Supporting Evidence: PMID:22727702 CED-7 and TTR-52 may promote the efflux of PS from apoptotic cells through the generation of extracellular PS vesicles |
| GO:0070986 left/right axis specification | IGI PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | REMOVE | Summary: Left/right axis specification (IGI with mom-5, Cabello et al. 2010). Reason: Full text read. The left/right axis specification (read out as ABar spindle orientation) phenotypes in this paper depend on MOM-5/Frizzled, GSK-3, beta-catenins and CED-10. The authors state that apart from ced-10 none of the other ced genes showed a strong defect. ced-7 is not in the one genotype with rare defects (ced-1; ced-5 double mutants), so there is no positive evidence for ced-7 in this process; the paper's own statement contradicts it. Same action as for ced-6 and ced-12; ced-1 and ced-5, which are in that double mutant, are marked over-annotated instead. Supporting Evidence: PMID:20126385 neither apr-1 nor any of the other ced genes showed a strong defect, suggesting that the link to CED-10 may not occur through CED-2/5/12 as is the case for engulfment and DTC migration |
| GO:0140359 ABC-type transporter activity | IEA GO_REF:0000002 | ACCEPT | Summary: ABC-type transporter activity, from InterPro. Reason: The most specific accurate molecular function for CED-7, from its ABCA domain architecture. The substrate is not established biochemically; genetic data point to phospholipid (PS) efflux. Supporting Evidence: PMID:9635425 the CED-7 protein has sequence similarity to ABC transporters, is broadly expressed during embryogenesis, and is localized to the plasma membrane PMID:22727702 CED-7 and TTR-52 may promote the efflux of PS from apoptotic cells through the generation of extracellular PS vesicles |
| GO:1901076 positive regulation of engulfment of apoptotic cell | IGI PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | MODIFY | Summary: Positive regulation of engulfment of apoptotic cell (IGI with mom-5, Cabello et al. 2010). Reason: CED-7 is a component of the CED-1/6/7 engulfment pathway, not an external regulator. It is required for CED-1 clustering and actin reorganization around corpses, and ced-7 single mutants have engulfment defects in this paper. Engulfment of apoptotic cell is the accurate term, matching the ced-1 and ced-6 reviews. Proposed replacements: engulfment of apoptotic cell Supporting Evidence: PMID:20126385 ced-1, ced-7, or ced-6 single mutants showed a weaker engulfment defect PMID:11163239 CED-1 failed to cluster around cell corpses in mutants defective in the engulfment gene ced-7 PMID:15744306 CED-1, CED-6 and CED-7 are required for actin reorganization around the apoptotic cell corpse |
| GO:1901076 positive regulation of engulfment of apoptotic cell | IMP PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | MODIFY | Summary: Positive regulation of engulfment of apoptotic cell (Cabello et al. 2010). Reason: As for the IGI row from this paper: the direct process term is the accurate one. Proposed replacements: engulfment of apoptotic cell Supporting Evidence: PMID:20126385 ced-1, ced-7, or ced-6 single mutants showed a weaker engulfment defect PMID:9635425 The C. elegans gene ced-7 functions in the engulfment of cell corpses during programmed cell death |
| GO:1901076 positive regulation of engulfment of apoptotic cell | IMP PMID:9635425 The C. elegans cell corpse engulfment gene ced-7 encodes a p... | MODIFY | Summary: Positive regulation of engulfment of apoptotic cell (Cabello et al. 2010). Reason: As for the IGI row from this paper: the direct process term is the accurate one. Proposed replacements: engulfment of apoptotic cell Supporting Evidence: PMID:20126385 ced-1, ced-7, or ced-6 single mutants showed a weaker engulfment defect PMID:9635425 The C. elegans gene ced-7 functions in the engulfment of cell corpses during programmed cell death |
| GO:1902742 apoptotic process involved in development | IGI PMID:24225442 Caspase-mediated activation of Caenorhabditis elegans CED-8 ... | MODIFY | Summary: Apoptotic process involved in development (IGI with ced-8, Chen et al. 2013). Reason: In the full text ced-7 mutants are an engulfment-defective background used to test ced-8; the paper does not test ced-7 in apoptosis. Engulfment genes promote the death of weakly signalled cells (Reddien 2001; Hoeppner 2001), which is the positive regulation term, matching the ced-1 and ced-6 reviews. The replacement is GO:0043065 positive regulation of apoptotic process, without the developmental context of its precomposed child GO:1904747. Proposed replacements: positive regulation of apoptotic process Context of precomposed term: context dropped The replacement is unfolded from GO:1904747 positive regulation of apoptotic process involved in development to GO:0043065 (projects/INVOLVED_IN_PRECOMPOSITION.md, round 6); the sign correction (regulation, not participation) is unchanged. The developmental context is not carried: it is where the engulfment genes' pro-death role was measured (Reddien 2001; Hoeppner 2001), not a mechanism, and the role is non-core for this gene. Supporting Evidence: PMID:24225442 only mildly enhanced the corpse engulfment defect of the ced-1, ced-6, ced-7 or ttr-52 mutants at the L1 larval stage PMID:11449278 mutations in engulfment genes enhance the frequency of this cell survival PMID:11449279 can also function to actively kill cells |
| GO:1902742 apoptotic process involved in development | IMP PMID:24225442 Caspase-mediated activation of Caenorhabditis elegans CED-8 ... | MODIFY | Summary: Apoptotic process involved in development (Chen et al. 2013). Reason: As for the IGI row: ced-7 is used as a clearance-defective background, so the process term is not supported, and the positive regulation term fits. The replacement is GO:0043065 positive regulation of apoptotic process, without the developmental context of its precomposed child GO:1904747. Proposed replacements: positive regulation of apoptotic process Context of precomposed term: context dropped The replacement is unfolded from GO:1904747 positive regulation of apoptotic process involved in development to GO:0043065 (projects/INVOLVED_IN_PRECOMPOSITION.md, round 6); the sign correction (regulation, not participation) is unchanged. The developmental context is not carried: it is where the engulfment genes' pro-death role was measured (Reddien 2001; Hoeppner 2001), not a mechanism, and the role is non-core for this gene. Supporting Evidence: PMID:24225442 only mildly enhanced the corpse engulfment defect of the ced-1, ced-6, ced-7 or ttr-52 mutants at the L1 larval stage PMID:11449278 mutations in engulfment genes enhance the frequency of this cell survival PMID:11449279 can also function to actively kill cells |
| GO:1903356 positive regulation of distal tip cell migration | IGI PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | MARK AS OVER ANNOTATED | Summary: Positive regulation of distal tip cell migration (IGI with mom-5, Cabello et al. 2010). Reason: The source paper concludes that the CED-1/6/7 pathway plays at most a minor role, if any, in distal tip cell migration. Supporting Evidence: PMID:20126385 we found that the CED-1/6/7 pathway appears to play at most a minor role, if any, in this process |
| 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: Positive regulation of apoptotic process involved in development (Denning et al. 2013). Reason: The cited paper uses ced-7 as a background that preserves corpses for counting, so it does not itself show this. The term is supported by Reddien et al. 2001, whose abstract defines its engulfment genes as ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 and states that mutations in engulfment genes alone allow some cells that would normally die to survive, and by Hoeppner et al. 2001. The role is non-core, a consequence of the engulfment role. The claim is positive regulation of apoptotic process (GO:0043065); the precomposed term's developmental context is dropped. Proposed replacements: positive regulation of apoptotic process Context of precomposed term: context dropped Decomposed from the precomposed GO:1904747 positive regulation of apoptotic process involved in development (projects/INVOLVED_IN_PRECOMPOSITION.md, round 6), which positively regulates GO:1902742 apoptotic process involved in development, to the regulation genus GO:0043065. The developmental context is not carried: it is where the engulfment genes' pro-death role was measured (Reddien 2001; Hoeppner 2001), not a mechanism, and the role is non-core for this gene. Supporting Evidence: PMID:23505386 we used mutations (e.g., ced-1(e1735), ced-6(n2095) or ced-7(n1996)) that cause defects in cell-corpse engulfment and result in the persistence of many embryonic cell corpses into larval stages PMID:11449278 the engulfment of dying cells requires the genes ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 PMID:11449278 mutations in engulfment genes alone allow the survival and differentiation of some cells that would normally die PMID:11449279 genes that mediate corpse removal can also function to actively kill cells |
| GO:1904747 positive regulation of apoptotic process involved in development | IGI PMID:23505386 Both the caspase CSP-1 and a caspase-independent pathway pro... | MODIFY | Summary: Positive regulation of apoptotic process involved in development (Denning et al. 2013). Reason: The cited paper uses ced-7 as a background that preserves corpses for counting, so it does not itself show this. The term is supported by Reddien et al. 2001, whose abstract defines its engulfment genes as ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 and states that mutations in engulfment genes alone allow some cells that would normally die to survive, and by Hoeppner et al. 2001. The role is non-core, a consequence of the engulfment role. The claim is positive regulation of apoptotic process (GO:0043065); the precomposed term's developmental context is dropped. Proposed replacements: positive regulation of apoptotic process Context of precomposed term: context dropped Decomposed from the precomposed GO:1904747 positive regulation of apoptotic process involved in development (projects/INVOLVED_IN_PRECOMPOSITION.md, round 6), which positively regulates GO:1902742 apoptotic process involved in development, to the regulation genus GO:0043065. The developmental context is not carried: it is where the engulfment genes' pro-death role was measured (Reddien 2001; Hoeppner 2001), not a mechanism, and the role is non-core for this gene. Supporting Evidence: PMID:23505386 we used mutations (e.g., ced-1(e1735), ced-6(n2095) or ced-7(n1996)) that cause defects in cell-corpse engulfment and result in the persistence of many embryonic cell corpses into larval stages PMID:11449278 the engulfment of dying cells requires the genes ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 PMID:11449278 mutations in engulfment genes alone allow the survival and differentiation of some cells that would normally die PMID:11449279 genes that mediate corpse removal can also function to actively kill cells |
| 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: Positive regulation of apoptotic process involved in development (Denning et al. 2013). Reason: The cited paper uses ced-7 as a background that preserves corpses for counting, so it does not itself show this. The term is supported by Reddien et al. 2001, whose abstract defines its engulfment genes as ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 and states that mutations in engulfment genes alone allow some cells that would normally die to survive, and by Hoeppner et al. 2001. The role is non-core, a consequence of the engulfment role. The claim is positive regulation of apoptotic process (GO:0043065); the precomposed term's developmental context is dropped. Proposed replacements: positive regulation of apoptotic process Context of precomposed term: context dropped Decomposed from the precomposed GO:1904747 positive regulation of apoptotic process involved in development (projects/INVOLVED_IN_PRECOMPOSITION.md, round 6), which positively regulates GO:1902742 apoptotic process involved in development, to the regulation genus GO:0043065. The developmental context is not carried: it is where the engulfment genes' pro-death role was measured (Reddien 2001; Hoeppner 2001), not a mechanism, and the role is non-core for this gene. Supporting Evidence: PMID:23505386 we used mutations (e.g., ced-1(e1735), ced-6(n2095) or ced-7(n1996)) that cause defects in cell-corpse engulfment and result in the persistence of many embryonic cell corpses into larval stages PMID:11449278 the engulfment of dying cells requires the genes ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 PMID:11449278 mutations in engulfment genes alone allow the survival and differentiation of some cells that would normally die PMID:11449279 genes that mediate corpse removal can also function to actively kill cells |
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Download this section (compressed HTML)Q: Does CED-7 transport phosphatidylserine itself, or does it move another lipid that drives PS-vesicle release? No reconstituted transport assay exists for CED-7.
Q: What does CED-7 do in the dying cell versus the engulfing cell, given that mosaic analysis shows a requirement in both?
Experiment: Express Walker A mutant CED-7 in ced-7 null embryos, in dying cells or engulfing cells only, and score sAnxV::GFP loss from corpses, extracellular PS vesicles by immuno-EM, and CED-1::GFP clustering.
Hypothesis: CED-7 ATPase activity is required for PS-vesicle release from apoptotic cells and for CED-1 clustering.
Type: genetic
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