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Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans

Abstract

The removal of apoptotic cells is essential for the physiological well being of the organism1,2,3. In Caenorhabditis elegans, two conserved, partially redundant genetic pathways regulate this process4,5,6. In the first pathway, the proteins CED-2, CED-5 and CED-12 (mammalian homologues CrkII, Dock180 and ELMO, respectively) function to activate CED-10 (Rac1)7,8. In the second group, the candidate receptor CED-1 (CD91/LRP/SREC) probably recognizes an unknown ligand on the apoptotic cell9 and signals via its cytoplasmic tail to the adaptor protein CED-6 (hCED-6/GULP)10,11, whereas CED-7 (ABCA1) is thought to play a role in membrane dynamics12. Molecular understanding of how the second pathway promotes engulfment of the apoptotic cell is lacking. Here, we show that CED-1, CED-6 and CED-7 are required for actin reorganization around the apoptotic cell corpse, and that CED-1 and CED-6 colocalize with each other and with actin around the dead cell. Furthermore, we find that the CED-10(Rac) GTPase acts genetically downstream of these proteins to mediate corpse removal, functionally linking the two engulfment pathways and identifying the CED-1, -6 and -7 signalling module as upstream regulators of Rac activation.

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Figure 1: Recruitment of actin halos around apoptotic cells in the hermaphrodite germ line requires CED-1 and CED-7.
Figure 2: CED-1 recruits CED-6 and actin around the apoptotic cell.

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Acknowledgements

We would like to thank K. S. Ravichandran, M. Spector, T. Gumienny and L. Stergiou for comments on this manuscript, S. Milstein for the use of the gla-1(op234) allele, O. Hobert for the gift of the Plim-7 plasmid, J. Austin for pDPMM0016 (unc-119(+ )), and P. Gisler for worm freezing. Some strains were supplied by the Caenorhabditis Genetic Center (CGC), which is supported by the National Institute of Health National Center for Research Resources. This work was supported by grants from the Swiss National Science Foundation, The Ernst Hadorn Foundation and the European Union (FP5 project APOCLEAR) to M.O.H., and by the Max Planck Society and an EU TMR Research Network grant to R.S.

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Correspondence to Michael O. Hengartner.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Methods

Additional description of methods used in paper. (DOC 23 kb)

Supplementary References

List of publications referenced in supplementary methods. (DOC 21 kb)

Supplementary Table 1

SYTO12 and SYTO41 specifically stain apoptotic cells in the hermaphrodite gonad. (DOC 23 kb)

Supplementary Table 2

CED-1 and CED-6 fusion proteins are functional. This table shows the ability of various transgenics to rescue the engulfment defects associated with various mutations to show functionality of FP-fusion proteins. (DOC 25 kb)

Supplementary Table 3

Overexpression of CED-10 cannot induce the formation of exogenous actin haloes. (DOC 25 kb)

Supplementary Table 4

Locations of lesions in genes used in Table 2 for double mutant analysis. (DOC 41 kb)

Supplementary Table 5

Corpses are still removed in a ced-10(t1875) mutant background. 4-D microscopy during embryogenesis in wild-type versuss ced-10(t1875) mutant worms suggests that although CED-10 is required for both engulfment pathway function, it is not required for engulfment per se, and a third salvage pathway may exist for the removal of apoptotic cell corpses. (DOC 52 kb)

Supplementary Table 6

Primers used for this study. (DOC 23 kb)

Supplementary Figure 1

YFP::Actin forms fibrous structures in the hermaphrodite somatic gonad. (DOC 354 kb)

Supplementary Figure 2

SYTO12 and SYTO41 specifically stain apoptotic cell corpses. (DOC 179 kb)

Supplementary Figure 3

CED-1 does not co-localize with actin fibers in the hermaphrodite somatic gonad. (DOC 75 kb)

Supplementary Figure 4

ced-10(t1875) has a mutated start codon. Diagram of lesions in the ced-10 locus used in this study, both at the DNA and at the protein level. (DOC 118 kb)

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Kinchen, J., Cabello, J., Klingele, D. et al. Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans. Nature 434, 93–99 (2005). https://doi.org/10.1038/nature03263

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