BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module
BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module
复制标题
DOI：
10.1038/nature06329
复制
发表时间：
2007-11-15
期刊：
影响因子：
64.8
通讯作者：
Ravichandran, Kodi S.
中科院分区：
文献类型：
--
作者：
Park, Daeho;Tosello-Trampont, Annie-Carole;Ravichandran, Kodi S.
凋亡细胞的吞噬和随后的降解是在所有多细胞生物体的整个生命过程中发生的重要步骤（1-3）。埃尔莫/ Dock（180）/Rac蛋白是促进凋亡细胞尸体内化的保守信号传导模块（4，5）;埃尔莫和Dock 180一起作为小GT3 Rac的鸟嘌呤核苷酸交换因子（GEF）发挥作用，从而在吞噬期间调节吞噬细胞肌动蛋白细胞骨架（4 - 6）。然而，埃尔莫/Dock 180/ Rac模块上游的受体仍然未知。在这里，我们确定脑特异性血管生成抑制因子1（BAI 1）作为受体上游的埃尔莫和作为受体，可以结合磷脂酰丝氨酸对凋亡细胞。BAI 1是属于粘附型G蛋白偶联受体家族的七跨膜蛋白，具有延伸的胞外区（7-9）并且没有已知的配体。我们发现，BAI 1功能作为一个吞噬受体的识别和随后的内化凋亡细胞。通过多线研究，我们鉴定了磷脂酰丝氨酸，一种暴露在凋亡细胞上的关键“吃我”信号（10-13），作为BAI 1的配体。BAI 1细胞外区域内的1型血小板反应蛋白重复序列介导与磷脂酰丝氨酸的直接结合。与细胞内信号传导一样，BAI 1与埃尔莫和Dock 180形成三聚体复合物，并且功能研究表明BAI 1与埃尔莫/Dock 180/Rac协作以促进凋亡细胞的最大吞噬。最后，降低BAI 1表达或干扰BAI 1功能可抑制离体和体内凋亡靶点的吞噬。因此，BAI 1是一种磷脂酰丝氨酸识别受体，可以直接募集Rac-GEF复合物来介导凋亡细胞的摄取。
Engulfment and subsequent degradation of apoptotic cells is an essential step that occurs throughout life in all multicellular organisms(1-3). ELMO/ Dock(180)/Rac proteins are a conserved signalling module for promoting the internalization of apoptotic cell corpses(4,5); 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(4 -6). 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(7-9) 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(10-13), 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.