Journey to the grave: signaling events regulating removal of apoptotic cells

Abstract

Programmed cell death is critical both for organ formation during development and during adult life, when billions of cells must be removed every day. The culmination of the apoptotic process is the specific recognition and engulfment of the apoptotic cell by a phagocyte. A number of recent studies have revealed a series of evolutionarily conserved proteins that link corpse recognition to membrane movement, facilitating the internalization of the target and its subsequent degradation. Two potential signaling modules have been identified: one involving the CED-12/ELMO and CED-5/Dock180 proteins, which function as a bipartite guanine nucleotide exchange factor (GEF) for Rac1, and a second involving CED-1/LRP1 (a potential engulfment receptor) and the adaptor protein CED-6/GULP. Recognition of the apoptotic cell modulates cytokine secretion by the phagocyte, resulting in an anti-inflammatory state distinct from that induced by necrotic cells. The recent molecular delineation of the phagocytic process and the identification of novel signaling proteins involved in engulfment have provided an exciting new platform for future studies into this biologically important process.

A pathway for phagosome maturation during engulfment of apoptotic cells

“…These results suggested that DYN-1 is recruited to the apoptotic cell following recognition and at a late stage during or following internalization of the corpse. Earlier studies have proposed that the ced-2, -5, -12 pathway was dispensable for DYN-1 recruitment during embryogenesis 62 ; however, this work utilized a group of cells that require a single pathway (comprised of ced-1, -6, -7) for efficient corpse internalization, whereas the adult hermaphrodite gonads uses both pathways for corpse removal 30,35 . Our more rigorous analysis suggests that the coordinated activity of both engulfment pathways results in recruitment of DYN-1 to the phagosome.…”

“…In the second pathway, two transmembrane proteins, CED-1/LRP1/MEGF10 20 Ã 22 and CED-7/ABCA1/ ABCA7 23 Ã 25 , may mediate recognition of the apoptotic cell and function upstream of the adapter protein CED-6/GULP 21,26 ; these proteins have also been suggested to signal to CED-10/Rac1 during engulfment 27,28 . Activation of CED-10/Rac1 promotes rearrangement of the actin cytoskeleton, permitting pseudopod extension around the apoptotic prey and ultimately internalization of the cell corpse into a membrane bound phagosome 29,30 .Studies in mammalian cells and in model organisms have shed light on the early steps of engulfment, such as the recognition and internalization of dying cells, but the identity of proteins required for subsequent steps, such as the maturation of phagosomes containing apoptotic cells into acidic structures, remain unclear. Proteomic approaches using latex beads internalized by cultured cells have identified a large number of phagosome-associated proteins 31 .…”

“…In the second pathway, two transmembrane proteins, CED-1/LRP1/MEGF10 20 Ã 22 and CED-7/ABCA1/ ABCA7 23 Ã 25 , may mediate recognition of the apoptotic cell and function upstream of the adapter protein CED-6/GULP 21,26 ; these proteins have also been suggested to signal to CED-10/Rac1 during engulfment 27,28 . Activation of CED-10/Rac1 promotes rearrangement of the actin cytoskeleton, permitting pseudopod extension around the apoptotic prey and ultimately internalization of the cell corpse into a membrane bound phagosome 29,30 .…”

Signalling Pathway Involving GULP, MAPK and Rac1 for SR-BI-Induced Phagocytosis of Apoptotic Cells

“…One pathway consists of the phagocytosis receptor CED-1, the adaptor protein CED-6 and the Rho family small G protein CED-10, while the other is composed of the adaptor CED-2, the signal mediators CED-5 and CED-12 and CED-10 (15-18); the two pathways seem to converge at CED-10 (19). All these CED proteins have counterparts in Drosophila and mammals, suggesting that the two signalling pathways are evolutionally conserved beyond species (18,20). In the present study, we examined which of the two pathways is adopted for the phagocytosis initiated by SR-BI.…”

DNA Degradation and Its Defects

“…The apoptotic cells tethered by Tim4 are transferred to a v b 3 integrin or MER receptor tyrosine kinases of the TAM family via PtdSer-binding opsonins, such as MFG-E8 and Gas6 that are secreted from macrophages (Scott et al 2001;Hanayama et al 2002;Xiong et al 2008). Apoptotic cells are then internalized by macrophages via "phagocytic cups" assembled by Rac1-dependent actin polymerization (Kinchen and Ravichandran 2007;Nakaya et al 2008), and are transported into lysosomes via early endosomes by the small GTPase Rab5 . Lysosomes contain a variety of degradative enzymes ( proteases, glycosidases, lipases, and nucleases) that digest components from dead cells into building units for reuse (amino acids, sugars, fatty acids, and nucleotides) (von Figura and Hasilik 1986).…”