Abstract
Clearance of apoptotic cells by engulfment plays an important role in the homeostasis and development of multicellular organisms. Despite the fact that the recognition of apoptotic cells by engulfment receptors is critical in inducing the engulfment process, the molecular mechanisms are still poorly understood. Here, we characterize a novel cell corpse engulfment pathway mediated by the integrin α subunit PAT-2 in Caenorhabditis elegans and show that it specifically functions in muscle-mediated engulfment during embryogenesis. Inactivation of pat-2 results in a defect in apoptotic cell internalization. The PAT-2 extracellular region binds to the surface of apoptotic cells in vivo, and the intracellular region may mediate signaling for engulfment. We identify essential roles of small GTPase CDC-42 and its activator UIG-1, a guanine-nucleotide exchange factor, in PAT-2–mediated cell corpse removal. PAT-2 and CDC-42 both function in muscle cells for apoptotic cell removal and are co-localized in growing muscle pseudopods around apoptotic cells. Our data suggest that PAT-2 functions through UIG-1 for CDC-42 activation, which in turn leads to cytoskeletal rearrangement and apoptotic cell internalization by muscle cells. Moreover, in contrast to PAT-2, the other integrin α subunit INA-1 and the engulfment receptor CED-1, which signal through the conserved signaling molecules CED-5 (DOCK180)/CED-12 (ELMO) or CED-6 (GULP) respectively, preferentially act in epithelial cells to mediate cell corpse removal during mid-embryogenesis. Our results show that different engulfing cells utilize distinct repertoires of receptors for engulfment at the whole organism level.
Highlights
During the development of multicellular organisms, cells that are unnecessary, damaged, or harmful undergo programmed cell death [1]
CED-1 binds to an apoptotic cell through secreted molecule TTR-52 and transduces. Their corpses are quickly recognized and phagocytosed by engulfing cells. Many cell types, such as muscle cells and epithelial cells, possess the ability to remove apoptotic cells, little is known about the receptors and signaling pathways used for apoptotic cell uptake by these ‘‘amateur’’ phagocytes
In Caenorhabditis elegans, integrin PAT-2/ PAT-3 functions as an engulfment receptor in muscle cells
Summary
During the development of multicellular organisms, cells that are unnecessary, damaged, or harmful undergo programmed cell death (apoptosis) [1]. Several mammalian receptors involved in apoptotic cell engulfment have been identified and characterized. Receptors such as BAI1 [15], stabilin-1 [16], stabilin-2 [17], TIM-1 [18], TIM-3 [19], TIM-4 [18], integrins [20,21], and receptor tyrosine kinase Mer [22] bind to the ‘‘eat me’’ signal, externalized phosphatidylserine (PS) [23,24], on the surface of apoptotic cells either directly [25,26] or through bridging molecules [27,28]. The in vivo role of most of these receptors in the clearance of apoptotic cells and the tissues in which they act at the whole organism level have not been defined
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