title: BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module.
abstract: 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.
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Daeho
authors.initials: D
authors.lastname: Park
authors.forename: Annie-Carole
authors.initials: AC
authors.lastname: Tosello-Trampont
authors.forename: Michael R
authors.initials: MR
authors.lastname: Elliott
authors.forename: Mingjian
authors.initials: M
authors.lastname: Lu
authors.forename: Lisa B
authors.initials: LB
authors.lastname: Haney
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ma
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Klibanov
authors.forename: James W
authors.initials: JW
authors.lastname: Mandell
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C524949:Adgrb1 protein, mouse; D042501:Angiogenic Proteins; C510359:ELMO1 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D008024:Ligands; D010718:Phosphatidylserines; D020744:rac GTP-Binding Proteins