Park, D, Tosello-Trampont, AC, Elliott, MR, Lu, M, Haney, LB, Ma, Z et al.. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450: 430-434

Department of Cell Biology, University of Virginia, Charlottesville, Virginia 22908, USA.
Nature (Impact Factor: 41.46). 12/2007; 450(7168):430-4. DOI: 10.1038/nature06329
Source: PubMed


Engulfment and subsequent degradation of apoptotic cells is an essential step that occurs throughout life in all multicellular organisms. ELMO/Dock180/Rac proteins are a conserved signalling module for promoting the internalization of apoptotic cell corpses; ELMO and Dock180 function together as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac, and thereby regulate the phagocyte actin cytoskeleton during engulfment. However, the receptor(s) upstream of the ELMO/Dock180/Rac module are still unknown. Here we identify brain-specific angiogenesis inhibitor 1 (BAI1) as a receptor upstream of ELMO and as a receptor that can bind phosphatidylserine on apoptotic cells. BAI1 is a seven-transmembrane protein belonging to the adhesion-type G-protein-coupled receptor family, with an extended extracellular region and no known ligands. We show that BAI1 functions as an engulfment receptor in both the recognition and subsequent internalization of apoptotic cells. Through multiple lines of investigation, we identify phosphatidylserine, a key 'eat-me' signal exposed on apoptotic cells, as a ligand for BAI1. The thrombospondin type 1 repeats within the extracellular region of BAI1 mediate direct binding to phosphatidylserine. As with intracellular signalling, BAI1 forms a trimeric complex with ELMO and Dock180, and functional studies suggest that BAI1 cooperates with ELMO/Dock180/Rac to promote maximal engulfment of apoptotic cells. Last, decreased BAI1 expression or interference with BAI1 function inhibits the engulfment of apoptotic targets ex vivo and in vivo. Thus, BAI1 is a phosphatidylserine recognition receptor that can directly recruit a Rac-GEF complex to mediate the uptake of apoptotic cells.

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    • "Thus far, a few receptors that bind directly to this aminophospholipid have been identified (Miyanishi et al., 2007; Park et al., 2007; 2008). Upon recognition, apoptotic cells trigger intracellular signaling pathways, thereby stimulating cytoskeletal rearrangement to draw apoptotic cells into phagocytes (Albert et al., 2000; Lee et al., 2014; Park et al., 2007). Finally, ingested apoptotic cells within phagocytes are degraded in phagolysosomes by digestive enzymes derived from lysosomes. "
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    • "More recently, Mazaheri et al. (2014) have used transgenic secA5 expression in live imaging studies as well to visualize PS exposure and clearance of dying neurons. In their study they use secA5 labeling of dying neurons to study the genes bai1 and tim4, previously implicated in vitro in recognition and adhesion of apoptotic cells (Kobayashi et al., 2007; Miyanishi et al., 2007; Park et al., 2007). They show that the in vivo functions of these two genes, is actually different from their function in vitro, as bai1 and tim4 control phagosome formation around dying neurons and stabilization of this phagosome. "
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