CED-6 is the C. elegans orthologue of mammalian GULP1, a cytoplasmic adaptor protein with an N-terminal phosphotyrosine-binding (PTB) domain, an adjacent leucine zipper that mediates homodimerization, and a proline/serine-rich C-terminal half. It acts in engulfing cells, where its PTB domain binds the NPXY motif in the cytoplasmic tail of the engulfment receptor CED-1. CED-6 is recruited with CED-1 around apoptotic cell corpses and, together with CED-7, it is needed for actin reorganization and corpse engulfment. It forms a complex with clathrin heavy chain and the AP2 adaptor complex on nascent phagosomes and acts upstream of dynamin DYN-1 and the Rac GTPase CED-10. CED-6 also recruits the E3 ubiquitin ligase TRIM-21 to CED-1, which leads to proteasomal turnover of the receptor. Like other engulfment genes, ced-6 helps engulfing cells promote the death of cells that receive weak death signals, and it contributes to the loss of dopaminergic neurons damaged by oxidative stress.
| 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-6 is not in the one genotype with rare defects (ced-1; ced-5 double mutants), so there is no positive evidence for ced-6 in this process; the paper's own statement contradicts it. Same action as for ced-7 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:0005124 scavenger receptor binding | IPI PMID:11729193 Interaction of CED-6/GULP, an adapter protein involved in en... | ACCEPT | Summary: Binds the cytoplasmic tail of the CED-1 engulfment receptor (Su et al. 2002). Reason: CED-1 is a class F scavenger receptor, and CED-6 binds its NPXY motif through its PTB domain. This was later confirmed by pull-down and yeast two-hybrid with NPXY and PTB mutants (Ma et al. 2022). The binding is the receptor-proximal step of the adaptor function captured in core_functions. Supporting Evidence: PMID:11729193 we present evidence for a physical interaction between GULP/CED-6 and one of the two motifs (NPXY motif) in the cytoplasmic tail of CED-1 PMID:11729193 The phosphotyrosine binding domain of GULP was necessary and sufficient for this interaction PMID:35929733 The CED-6 and CED-1-CT interaction depends on CED-1-CT NPXY motif and the CED-6 PTB domain |
| GO:0005515 protein binding | IPI PMID:11729193 Interaction of CED-6/GULP, an adapter protein involved in en... | MODIFY | Summary: Protein binding with CED-1 (Q9XWD6) from the same paper as the scavenger receptor binding row. Reason: Uninformative term. The interaction is the PTB-domain binding of CED-6 to the CED-1 NPXY motif, which relays the engulfment signal from the receptor to downstream effectors. Signaling adaptor activity describes that role. Scavenger receptor binding is already annotated separately from the same evidence. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:11729193 we present evidence for a physical interaction between GULP/CED-6 and one of the two motifs (NPXY motif) in the cytoplasmic tail of CED-1 PMID:9635426 Our data suggest that CED-6 is an adaptor molecule acting in a signal transduction pathway that specifically mediates the recognition and engulfment of apoptotic cells |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasm, from the UniProt subcellular location mapping. Reason: CED-6 has no transmembrane segment or signal peptide and is a cytoplasmic adaptor. It is recruited from the cytoplasm to the inner face of the membrane around corpses, which the more specific location terms capture. Supporting Evidence: PMID:15744306 CED-1 and CED-6 colocalize with each other and with actin around the dead cell |
| GO:0009898 cytoplasmic side of plasma membrane | IDA PMID:15744306 Two pathways converge at CED-10 to mediate actin rearrangeme... | ACCEPT | Summary: Cytoplasmic side of the plasma membrane, around apoptotic cell corpses (Kinchen et al. 2005). Reason: CED-6 colocalizes with the CED-1 receptor tail and actin at the engulfing-cell membrane that surrounds the corpse. That is the cytoplasmic face of the plasma membrane at the phagocytic cup. Supporting Evidence: PMID:15744306 CED-1 and CED-6 colocalize with each other and with actin around the dead cell |
| GO:0012501 programmed cell death | IMP PMID:9635426 Candidate adaptor protein CED-6 promotes the engulfment of a... | MARK AS OVER ANNOTATED | Summary: Programmed cell death, from the ced-6 cloning paper (Liu and Hengartner 1998). Reason: The phenotype in this paper is persistent corpses caused by failed engulfment. CED-6 acts in the engulfing cell, not in the dying cell, so the mutant phenotype reflects corpse clearance rather than the death program. Engulfment genes do promote death of weakly signalled cells, but that is better captured by the positive regulation term, which this gene already carries. Supporting Evidence: PMID:9635426 Genetic mosaic analysis demonstrates that ced-6 acts within engulfing cells PMID:11449278 mutations in engulfment genes enhance the frequency of this cell survival |
| GO:0016192 vesicle-mediated transport | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Vesicle-mediated transport, inferred from the clathrin-cargo adaptor activity annotation. Reason: This is a mechanical inference from GO:0035615. CED-6 forms a complex with clathrin and AP2 on phagosomes, but the evidence points to an actin-organizing hub for engulfment, not to transport by clathrin-coated vesicles. Engulfment of apoptotic cell already captures the process. Supporting Evidence: PMID:23696751 we propose that the formation of a protein complex by CED-1, CED-6, AP2 and CHC-1 provides a hub for recruitment and assembly of actin for cell corpse engulfment |
| GO:0035615 clathrin-cargo adaptor activity | IPI PMID:23696751 Clathrin and AP2 are required for phagocytic receptor-mediat... | KEEP AS NON CORE | Summary: Clathrin-cargo adaptor activity, from CED-6 binding to clathrin heavy chain and AP2 subunits (Chen et al. 2013). Reason: The binding is direct (pull-downs and co-IP), and CED-6 binds both the receptor CED-1 and clathrin, which matches the literal definition. However, the authors propose that the CED-1/CED-6/AP2/clathrin complex organizes actin at the corpse, not that CED-6 loads cargo into clathrin-coated vesicles. Kept as a non-core reading of the biochemistry. Signaling adaptor activity is the core function. Supporting Evidence: PMID:23696751 the CED-6 adaptor protein directly interacts with CHC-1 and individual components of the AP2 complex PMID:23696751 we propose that the formation of a protein complex by CED-1, CED-6, AP2 and CHC-1 provides a hub for recruitment and assembly of actin for cell corpse engulfment |
| GO:0043277 apoptotic cell clearance | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Apoptotic cell clearance (ARBA). Reason: Correct but general: the parent of engulfment of apoptotic cell, which is the specific, directly supported process and is carried in core_functions. Supporting Evidence: PMID:9635426 Our data suggest that CED-6 is an adaptor molecule acting in a signal transduction pathway that specifically mediates the recognition and engulfment of apoptotic cells |
| GO:0043652 engulfment of apoptotic cell | IMP PMID:9635426 Candidate adaptor protein CED-6 promotes the engulfment of a... | ACCEPT | Summary: Engulfment of apoptotic cell; ced-6 mutants fail to engulf corpses, and ced-6 acts in engulfing cells (Liu and Hengartner 1998). Reason: Core function. Mosaic analysis places ced-6 in engulfing cells, and CED-6 is needed for actin reorganization around corpses. It is the adaptor through which the CED-1 receptor signals to drive engulfment. Supporting Evidence: PMID:9635426 Genetic mosaic analysis demonstrates that ced-6 acts within engulfing cells PMID:9635426 ced-6 can promote the engulfment of cells at both early and late stages of apoptosis PMID:15744306 CED-1, CED-6 and CED-7 are required for actin reorganization around the apoptotic cell corpse |
| GO:0045335 phagocytic vesicle | IDA PMID:15744306 Two pathways converge at CED-10 to mediate actin rearrangeme... | ACCEPT | Summary: Phagocytic vesicle (Kinchen et al. 2005). Reason: CED-6 surrounds corpses together with CED-1 during engulfment. GFP::CED-6 is also recruited to germ-cell phagosomes (Chen et al. 2013). The localization is transient and is strongest at the forming phagosome. Supporting Evidence: PMID:15744306 CED-1 and CED-6 colocalize with each other and with actin around the dead cell |
| 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-6 is not in the one genotype with rare defects (ced-1; ced-5 double mutants), so there is no positive evidence for ced-6 in this process; the paper's own statement contradicts it. Same action as for ced-7 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: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-6 does not regulate engulfment from outside the process. It is the adaptor that relays the receptor signal and carries out engulfment, and ced-6 single mutants have engulfment defects in this paper. The direct process term is the accurate one, matching the ced-1 review. 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:9635426 Genetic mosaic analysis demonstrates that ced-6 acts within engulfing cells |
| 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: CED-6 is a component of the engulfment machinery, not an external regulator, so 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:9635426 Genetic mosaic analysis demonstrates that ced-6 acts within engulfing cells |
| 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-6(n2095) is an engulfment-defective background in which corpses persist and can be counted; the paper tests ced-8, not ced-6. Separately, engulfment genes including ced-6 promote the death of cells receiving weak death signals (Reddien 2001; Hoeppner 2001), acting from the engulfing cell. CED-6 therefore promotes death rather than taking part in the dying cell's apoptotic program, as for ced-1. 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 alone allow the survival and differentiation of some cells that would normally die PMID:11449278 requires the genes ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 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: Same as the IGI row: the ced-6 mutant is used as a clearance-defective background, and the death-promoting role of engulfment genes acts from the engulfing cell. 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 alone allow the survival and differentiation of some cells that would normally die 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, which depends on the CED-2/5/12 branch. 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-6 as a background that preserves corpses for counting, so it does not itself show this. The term is still supported: engulfment genes, ced-6 among them, promote the death of cells receiving weak death signals (Reddien 2001; Hoeppner 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 mutations in engulfment genes alone allow the survival and differentiation of some cells that would normally die PMID:11449278 requires the genes ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 PMID:11449278 mutations in engulfment genes enhance the frequency of this cell survival PMID:11449279 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: As for the IGI row: the paper uses ced-6 as a clearance-defective background, but the term is supported by Reddien 2001 and Hoeppner 2001. The role is non-core. 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 mutations in engulfment genes alone allow the survival and differentiation of some cells that would normally die PMID:11449278 mutations in engulfment genes enhance the frequency of this cell survival PMID:11449279 can also function to actively kill cells |
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Download this section (compressed HTML)Q: What are the direct effectors of CED-6 that link it to CED-10/Rac activation and to actin assembly, beyond the clathrin/AP2 hub?
Q: Does the CED-6-dependent recruitment of TRIM-21, which degrades CED-1, act as negative feedback that terminates engulfment signalling after each corpse?
Q: Is GO:0035615 clathrin-cargo adaptor activity appropriate for an adaptor whose clathrin/AP2 complex appears to organize actin rather than form coated vesicles?
Experiment: Tether the CED-6 PTB domain, or a PTB-dead CED-6, to the CED-1 tail in ced-6 null animals and score phagosomal CHC-1, APA-2 and actin recruitment and germ-cell corpse numbers.
Hypothesis: The CED-6 PTB-CED-1 NPXY interaction is sufficient to recruit the clathrin/AP2 hub and actin to the corpse.
Type: genetic
ced-6 encodes an Src homology (SH) 3 and phosphotyrosine-binding (PTB) domain-containing adaptor protein, orthologous to human CED-6/GULP, that is required for cell corpse engulfment during apoptosis; CED-6 is bound by the phosphotyrosine binding motif in the cytoplasmic tail of the transmembrane protein CED-1, and and within phagocytic cells this interaction may be part of a signal transduction pathway that promotes apoptotic cell engulfment.
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