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

The removal of apoptotic cells is essential for the physiological well being of the organism(1-3). In Caenorhabditis elegans, two conserved, partially redundant genetic pathways regulate this process(4-6). 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 cell(9) 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 dynamics(12). 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.