Identification of Tim4 as a phosphatidylserine receptor
Identification of Tim4 as a phosphatidylserine receptor
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DOI：
10.1038/nature06307
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发表时间：
2007-11-15
期刊：
影响因子：
64.8
通讯作者：
Nagata, Shigekazu
中科院分区：
文献类型：
--
作者：
Miyanishi, Masanori;Tada, Kazutoshi;Nagata, Shigekazu
在程序性细胞死亡中，大量细胞发生凋亡，并被巨噬细胞吞噬，以避免垂死细胞释放有毒物质(1,2)。在确定性红细胞生成过程中，细胞核从红系前体细胞中排出并被巨噬细胞吞噬。磷脂酰丝氨酸暴露在凋亡细胞表面(3) 和红系前体细胞排出的细胞核(4) 上；它充当吞噬细胞的“吃掉我”信号(5,6)。磷脂酰丝氨酸也在参与细胞间信号传导的外泌体表面表达 (7)。在这里，我们建立了抗小鼠腹腔巨噬细胞的仓鼠单克隆抗体库，并发现了一种强烈抑制凋亡细胞的磷脂酰丝氨酸依赖性吞噬的抗体。抗体识别的抗原通过表达克隆鉴定为 I 型跨膜蛋白，称为 Tim4（包含 T 细胞免疫球蛋白和粘蛋白结构域的分子；也称为 Timd4）(8)。 Tim4在多种小鼠组织的Mac1(+)细胞中表达，包括脾脏、淋巴结和胎肝。 Tim4 通过其免疫球蛋白结构域识别磷脂酰丝氨酸来结合凋亡细胞。 Tim4 在成纤维细胞中的表达增强了它们吞噬凋亡细胞的能力。当将抗Tim4单克隆抗体给予小鼠时，胸腺巨噬细胞对凋亡细胞的吞噬被显着阻断，小鼠产生自身抗体。在其他 Tim 家族成员中，Tim1 特异性结合磷脂酰丝氨酸，但 Tim2 和 Tim3 都没有。表达 Tim1 或 Tim4 的 Ba/F3 B 细胞通过磷脂酰丝氨酸与外泌体结合，外泌体刺激 Tim1 和 Tim4 之间的相互作用。这些结果表明Tim4和Tim1是吞噬凋亡细胞的磷脂酰丝氨酸受体，并且也可能参与外泌体参与的细胞间信号传导。
In programmed cell death, a large number of cells undergo apoptosis, and are engulfed by macrophages to avoid the release of noxious materials from the dying cells(1,2). In definitive erythropoiesis, nuclei are expelled from erythroid precursor cells and are engulfed by macrophages. Phosphatidylserine is exposed on the surface of apoptotic cells(3) and on the nuclei expelled from erythroid precursor cells(4); it works as an 'eat me' signal for phagocytes(5,6). Phosphatidylserine is also expressed on the surface of exosomes involved in intercellular signalling(7). Here we established a library of hamster monoclonal antibodies against mouse peritoneal macrophages, and found an antibody that strongly inhibited the phosphatidylserine-dependent engulfment of apoptotic cells. The antigen recognized by the antibody was identified by expression cloning as a type I transmembrane protein called Tim4 (T-cell immunoglobulin- and mucin-domain-containing molecule; also known as Timd4)(8). Tim4 was expressed in Mac1(+) cells in various mouse tissues, including spleen, lymph nodes and fetal liver. Tim4 bound apoptotic cells by recognizing phosphatidylserine via its immunoglobulin domain. The expression of Tim4 in fibroblasts enhanced their ability to engulf apoptotic cells. When the anti-Tim4 monoclonal antibody was administered into mice, the engulfment of apoptotic cells by thymic macrophages was significantly blocked, and the mice developed autoantibodies. Among the other Tim family members, Tim1, but neither Tim2 nor Tim3, specifically bound phosphatidylserine. Tim1- or Tim4-expressing Ba/F3 B cells were bound by exosomes via phosphatidylserine, and exosomes stimulated the interaction between Tim1 and Tim4. These results indicate that Tim4 and Tim1 are phosphatidylserine receptors for the engulfment of apoptotic cells, and may also be involved in intercellular signalling in which exosomes are involved.