title: Loss of the RhoGAP SRGP-1 promotes the clearance of dead and injured cells in Caenorhabditis elegans.
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.
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Lukas J
authors.initials: LJ
authors.lastname: Neukomm
authors.forename: Andreas P
authors.initials: AP
authors.lastname: Frei
authors.forename: Juan
authors.initials: J
authors.lastname: Cabello
authors.forename: Jason M
authors.initials: JM
authors.lastname: Kinchen
authors.forename: Ronen
authors.initials: R
authors.lastname: Zaidel-Bar
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ma
authors.forename: Lisa B
authors.initials: LB
authors.lastname: Haney
authors.forename: Jeff
authors.initials: J
authors.lastname: Hardin
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
authors.forename: Sergio
authors.initials: S
authors.lastname: Moreno
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hengartner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D010587:Phagocytosis; D011485:Protein Binding; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C407268:CED-10 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D020690:GTPase-Activating Proteins; C556127:SRGP-1 protein, C elegans; C085379:rho GTPase-activating protein; D049452:Green Fluorescent Proteins; D020744:rac GTP-Binding Proteins