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Loss of the RhoGAP SRGP-1 promotes the clearance of dead and injured cells in Caenorhabditis elegans

A Corrigendum to this article was published on 01 February 2011

Abstract

Multicellular animals rapidly clear dying cells from their bodies. Many of the pathways that mediate this cell removal are conserved through evolution. Here, we identify srgp-1 as a negative regulator of cell clearance in both Caenorhabditis elegans and mammalian cells. Loss of srgp-1 function results in improved engulfment of apoptotic cells, whereas srgp-1 overexpression inhibits apoptotic cell corpse removal. We show that SRGP-1 functions in engulfing cells and functions as a GTPase activating protein (GAP) for CED-10 (Rac1). Interestingly, loss of srgp-1 function promotes not only the clearance of already dead cells, but also the removal of cells that have been brought to the verge of death through sublethal apoptotic, necrotic or cytotoxic insults. In contrast, impaired engulfment allows damaged cells to escape clearance, which results in increased long-term survival. We propose that C. elegans uses the engulfment machinery as part of a primitive, but evolutionarily conserved, survey mechanism that identifies and removes unfit cells within a tissue.

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Figure 1: Loss of srgp-1 activity reduces the numbers of persistent apoptotic cell corpses in C. elegans.
Figure 2: SRGP-1 functions in the engulfing cell and antagonizes engulfment activity.
Figure 3: SRGP-1 (srGAP1) binds to and modulates CED-10 (Rac1) GTPase activity.
Figure 4: Enhanced engulfment promotes the removal of viable but sick cells in C. elegans.

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References

  1. Vaux, D. L. & Korsmeyer, S. J. Cell death in development. Cell 96, 245–254 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Debatin, K.M. Apoptosis pathways in cancer and cancer therapy. Cancer Immunol. Immunother. 53, 153–159 (2004).

    Article  PubMed  Google Scholar 

  3. Savill, J., Gregory, C. & Haslett, C. Eat me or die. Science 302, 1516–1517 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Fullard, J. F., Kale, A. & Baker, N. E. Clearance of apoptotic corpses. Apoptosis 14, 1029–1037 (2009).

    Article  PubMed  Google Scholar 

  5. Zhou, Z., Hartwieg, E. & Horvitz, H. R. CED-1 is a transmembrane receptor that mediates cell corpse engulfment in C. elegans. Cell 104, 43–56 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Wu, Y. C. & Horvitz, H. R. The C. elegans cell corpse engulfment gene ced-7 encodes a protein similar to ABC transporters. Cell 93, 951–960 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Yu, X., Odera, S., Chuang, C. H., Lu, N. & Zhou, Z. C. elegans dynamin mediates the signaling of phagocytic receptor CED-1 for the engulfment and degradation of apoptotic cells. Dev. Cell 10, 743–757 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Kinchen, J. M. et al. Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans. Nature 434, 93–99 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Liu, Q. A. & Hengartner, M. O. Candidate adaptor protein CED-6 promotes the engulfment of apoptotic cells in C. elegans. Cell 93, 961–972 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Gumienny, T. L. et al. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 107, 27–41 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Wu, Y. C. & Horvitz, H. R. C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180. Nature 392, 501–504 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. deBakker, C. D. et al. Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO. Curr. Biol. 14, 2208–2216 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Reddien, P. W. & Horvitz, H. R. CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nat. Cell Biol. 2, 131–136 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Akakura, S. et al. C-terminal SH3 domain of CrkII regulates the assembly and function of the DOCK180/ELMO Rac-GEF. J. Cell Physiol. 204, 344–351 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Tosello-Trampont, A. C. et al. Identification of two signaling submodules within the CrkII/ELMO/Dock180 pathway regulating engulfment of apoptotic cells. Cell Death Differ. 14, 963–972 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Hurwitz, M. E. et al. Abl kinase inhibits the engulfment of apoptotic cells in Caenorhabditis elegans. PLoS Biol. 7, e99 (2009).

    Article  PubMed  Google Scholar 

  17. Cabello, J. et al. The Wnt pathway controls cell death engulfment, spindle orientation, and migration through CED-10/Rac. PLoS Biol. 8, e1000297 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hsu, T. Y. & Wu, Y. C. Engulfment of apoptotic cells in C. elegans is mediated by integrin α/SRC signaling. Curr. Biol. 20, 477–486 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Rual, J. F. et al. Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res. 14, 2162–2168 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kamath, R. S. & Ahringer, J. Genome-wide RNAi screening in Caenorhabditis elegans. Methods 30, 313–321 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Sulston, J. E., Schierenberg, E., White, J. G. & Thomson, J. N. The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev. Biol. 100, 64–119 (1983).

    Article  CAS  PubMed  Google Scholar 

  22. Kinchen, J. & Ravichandran, K. Journey to the grave: signaling events regulating removal of apoptotic cells. J. Cell Sci. 120, 2143–2149 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Conradt, B. & Horvitz, H. R. The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl2like protein CED-9. Cell 93, 519–529 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Patel, F. B. et al. The WAVE/SCAR complex promotes polarized cell movements and actin enrichment in epithelia during C. elegans embryogenesis. Dev. Biol. 324, 297–309 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Barrett, T. et al. The structure of the GTPase-activating domain from p50rhoGAP. Nature 385, 458–461 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Park, D. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430–434 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Zaidel-Bar, R. et al. The F-BAR domain of SRGP-1 facilitates cell-cell adhesion during C. elegans morphogenesis. J. Cell Biol. 191, 761–769 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Blom, N., Gammeltoft, S. & Brunak, S. Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J. Mol. Biol. 294, 1351–1362 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Suetsugu, S., Toyooka, K. & Senju, Y. Subcellular membrane curvature mediated by the BAR domain superfamily proteins. Semin. Cell Dev. Biol. 21, 340–349 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Henne, W. M. et al. FCHo proteins are nucleators of clathrin-mediated endocytosis. Science 328, 1281–1284 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Guerrier, S. et al. The F-BAR domain of srGAP2 induces membrane protrusions required for neuronal migration and morphogenesis. Cell 138, 990–1004 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yang, Y., Lu, J., Rovnak, J., Quackenbush, S. L. & Lundquist, E. A. SWAN1, a Caenorhabditis elegans WD repeat protein of the AN11 family, is a negative regulator of Rac GTPase function. Genetics 174, 1917–1932 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zou, W. et al. Caenorhabditis elegans myotubularin MTM-1 negatively regulates the engulfment of apoptotic cells. PLoS Genet. 5, e1000679 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Reddien, P. W., Cameron, S. & Horvitz, H. R. Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198–202 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Hoeppner, D. J., Hengartner, M. O. & Schnabel, R. Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412, 202–206 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Chung, S., Gumienny, T. L., Hengartner, M. O. & Driscoll, M. A common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in C. elegans. Nat. Cell Biol. 2, 931–937 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Galvin, B. D., Kim, S. & Horvitz, H. R. Caenorhabditis elegans genes required for the engulfment of apoptotic corpses function in the cytotoxic cell deaths induced by mutations in lin-24 and lin-33. Genetics 179, 403–417 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mano, I. & Driscoll, M. DEG/ENaC channels: a touchy superfamily that watches its salt. Bioessays 21, 568–578 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Zhang, W. et al. Intersubunit interactions between mutant DEG/ENaCs induce synthetic neurotoxicity. Cell Death Differ. 15, 1794–1803 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Li, W. & Baker, N. E. Engulfment is required for cell competition. Cell 129, 1215–1225 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Sulston, J. E. & Horvitz, H. R. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev. Biol. 56, 110–156 (1977).

    Article  CAS  PubMed  Google Scholar 

  43. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).

    Article  CAS  PubMed  Google Scholar 

  44. Schnabel, R., Hutter, H., Moerman, D. & Schnabel, H. Assessing normal embryogenesis in Caenorhabditis elegans using a 4D microscope: variability of development and regional specification. Dev. Biol. 184, 234–265 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Tosello-Trampont, A.C., Nakada-Tsukui, K. & Ravichandran, K.S. Engulfment of apoptotic cells is negatively regulated by Rho-mediated signaling. J. Biol .Chem. 278, 49911–49919 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Kinchen, J. M. et al. A pathway for phagosome maturation during engulfment of apoptotic cells. Nat. Cell. Biol. 10, 556–566 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Elliott, M. R. et al. Unexpected requirement for ELMO1 in clearance of apoptotic germ cells in vivo. Nature 467, 333–337 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the Hengartner lab members for comments and discussions, M. Weiss for statistical advice and M. Jovanovic for assistance with in vivo pulldown experiments. Some strains were supplied by the Caenorhabditis Genetic Center (CGC), the C. elegans knock-out consortium (Oklahoma, USA) and the National Bioresource Project (Japan). This work was supported by grants from the American Heart Association and American Cancer Society (to J.M.K.), the NIGMS/NIH (to K.S.R., a William Benter Senior Fellow of the American Asthma Foundation), the Junta de Castilla y León (grant CSI03A08), the Spanish Ministry of Science and Innovation (grant BFU2010-21794) and the Riojasalud Foundation (to J.C.), the Junta de Castilla y León (Grupo de Excelencia GR265) and the Spanish Ministry of Science and Innovation (grants BFU200801808 and Consolider CSD200700015 to S.M.), the NIH postdoctoral training grant GM078747 and the fellowship from the Machiah Foundation (to R.Z.-B.), the Swiss National Science Foundation, The Ernst Hadorn Foundation and the European Union (FP5 project APOCLEAR to M.O.H.).

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L.J.N., A.P.F. and R.Z.B. contributed to the generation of nematode transgenics and fluorescence microscopy studies. A.P.F. and L.J.N. conducted the unbiased screen and the epistasis experiments. J.C. performed the 4D microscopic analysis. J.M.K. performed the mammalian cell culture experiments. Z.M. and L.B.H. performed the pulldowns and the hydrolysis assays. L.J.N. performed the cell-killing assay and wrote the manuscript. A.P.F. and M.O.H. contributed to the data analysis, project planning and writing of the manuscript. All authors contributed to editing the manuscript.

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Correspondence to Michael O. Hengartner.

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Neukomm, L., Frei, A., Cabello, J. et al. Loss of the RhoGAP SRGP-1 promotes the clearance of dead and injured cells in Caenorhabditis elegans. Nat Cell Biol 13, 79–86 (2011). https://doi.org/10.1038/ncb2138

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