Phagocytosis promotes programmed cell death and is controlled by Rac signaling pathway in C. elegans

Abstract

Programmed cell death is important in development, homeostasis, and disease. In the nematode Caenorhabditis elegans, four genes, egl-1, ced-9, ced-4, and ced-3, control the execution of cell death and define a molecular pathway for cell death conserved in humans. Seven genes control the engulfment of cell deaths and define two partially redundant pathways: ced-1, ced-6, and ced-7 in one pathway and ced-2, ced-5, ced-10, and ced-12 in the other. ced-3 encodes a defining member of a family of cysteine proteases termed caspases. We performed a mutational analysis of the ced-3 caspase-encoding gene, identified residues within the CED-3 protein important for caspase function in vivo, and determined that a limited amount of cell death can occur in the complete absence of CED-3 protease activity. We discovered a role for engulfment in promoting cell death and found that in the absence of engulfment, cells could occasionally recover from the initial stages of death that are triggered by the CED-3 caspase. Our results support a new view of cell death in which engulfing cells actively promote the death process rather than simply remove dead cells. We characterized an engulfment pathway and found that ced-2 encodes an adaptor protein similar to human CrkII that physically interacts with the previously identified CED-5 DOCK180 protein and that ced-10 encodes a Rac-like GTPase. ced-10 acts downstream of ced-2 and ced-5 within engulfing cells to control the extension of cell surfaces around dying cells.

(cont.) We found that ced-10 Rac is the primary Rac gene required for engulfment but acts redundantly with the mig-2 Rac-like gene and independently from ced-2 and ced-5 to control neuronal migration and axon pathfinding. We suggest Rac genes can be differentially utilized and regulated for different developmental events. We identified two new genes that promote programmed cell death from a genetic screen. The first, dpl-i, encodes a protein similar to human DP, which is the heterodimerization partner for the transcription factor E2F. The second, mcd-l, encodes a novel Zn finger-containing protein. dpl-l and mcd-l act downstream of the cell death inhibitory gene ced-9 to promote cell death.