The human homologue of Caenorhabditis elegans CED-6 specifically promotes phagocytosis of apoptotic cells

Abstract

A key feature of the process of programmed cell death (apoptosis) is the efficiency with which the dying cells are recognized and engulfed by phagocytes [1]. Apoptotic cells are rapidly cleared either by neighbouring cells acting as semi-professional phagocytes or by experts of the macrophage line, so that an inflammatory response is avoided [2]. The Caenorhabditis elegans gene ced-6 is required for efficient engulfment of apoptotic cells [3] and is one of a group of genes that define two partially redundant parallel pathways for the engulfment process [4] [5]. These pathways may be conserved across evolution, as two other engulfment genes have human homologues. A CED-5 homologue is part of a human CrkII-DOCK180-Rac signaling pathway proposed to mediate cytoskeletal reorganization [6] [7] [8] and a CED-7 homologue is similar to the ABC transporters [9] [10]. Here, we report the cloning and characterization of human CED-6, a human homologue of C. elegans CED-6. The 34 kDa hCED-6 protein is expressed in most tissues, some human cancer cells, and in primary human macrophages. We developed an assay that quantitates the phagocytic activity of mammalian macrophages: the number of apoptotic cells that have been internalized is measured by the uptake of lacZ-positive apoptotic cells by adherent transgenic macrophages. The results of this assay demonstrate that overexpression of hCED-6 promotes phagocytosis only of apoptotic cells and suggest that hCED-6 is the mammalian orthologue of C. elegans CED-6 and is a part of a highly conserved pathway that specifically mediates the phagocytosis of apoptotic cells.

The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62dok(Dok1) and activates NF-κB

“…Dock2 appears to be the Dock180 of hematopoietic lineage cells. Dock180 associates with Crk and p130Cas and is an important regulator of Rac, cell migration, and phagocytosis of apoptotic bodies (22,23,(45)(46)(47). Higher-level association of Dock2 with SH2D1A may require factors exclusively expressed in lymphoid tissues.…”

Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences

“…Furthermore, Albert and colleagues recently showed that stimulation of αvβ5 vitronectin receptor on DCs activates this pathway, and it is likely that other receptors will be found to activate this pathway (44). It is exciting to note also that ced-6 has a human homologue that is implicated in signaling for uptake in mammalian cells (58)(59)(60)(61). Combining the power of the genetic studies in C. elegans and Drosophila with the recognition and biochemical studies in mammalian cells has allowed the study of apoptotic cell clearance to finally make significant progress.…”

Rho GTPase signalling pathways in the morphological changes associated with apoptosis

“…106 Since ced-6 has been proposed to act as an adaptor molecule and does not possess an obvious catalytic domain, it is unclear whether it acts upstream or downstream of ced-10. 105,106,133,134 It is possible that the ced-1 pathway signals through an alternative Rac-like GTPase even in the presence of a ced-10 mutation since C. elegans express a Rac2 homologue 135 and a GTPase termed Mig-2 that is 64% identical to ced-10. 136 Interestingly, the scavenger receptor MARCO, which is involved in the macrophage clearance of bacteria, was recently shown to induce morphological changes associated with rearrangement of the actin cytoskeleton when overexpressed.…”