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

Nature Cell Biology volume 13, pages 79–86 (2011)Cite this article

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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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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.).

Author information

Author notes

  1. Lukas J. Neukomm

    Present address: Current address: Department of Neurobiology, Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.,

  2. Andreas P. Frei

    Present address: Current address: Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland.,

Authors and Affiliations

  1. Institute of Molecular Life Sciences, University of Zurich, Zurich, 8057, Switzerland

    Lukas J. Neukomm, Andreas P. Frei & Michael O. Hengartner

  2. Ph.D. Program in Molecular Life Sciences (MLS), University of Zurich/ETH Zurich, 8057 Zurich, Switzerland.,

    Andreas P. Frei

  3. Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, 37007, Salamanca, Spain

    Juan Cabello & Sergio Moreno

  4. Center for Biomedical Research of La Rioja (CIBIR), C/Piqueras 98, 26006, Logroño, Spain

    Juan Cabello

  5. Center for Cell Clearance and the Department of Microbiology, University of Virginia, Charlottesville, 22902, VA, USA

    Jason M. Kinchen, Zhong Ma, Lisa B. Haney & Kodi S. Ravichandran

  6. Department of Zoology, University of Wisconsin – Madison, 53706, WI, USA

    Ronen Zaidel-Bar & Jeff Hardin

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Contributions

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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