Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte
Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte
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DOI：
10.1016/j.cell.2005.08.032
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发表时间：
2005-10-21
期刊：
影响因子：
64.5
通讯作者：
Henson, PM
中科院分区：
文献类型：
--
作者：
Gardai, SJ;McPhillips, KA;Henson, PM
去除凋亡细胞对发育、组织内环境稳定和炎症消退至关重要。尽管存在许多候选系统，但只有磷脂酰丝氨酸被确定为凋亡细胞的通用识别配体。在这里，我们证明了钙网蛋白通过结合和激活吞噬细胞上的低密度脂蛋白受体相关蛋白(LRP)而起到第二种通用识别配体的作用。由于在活细胞上也发现了表面钙网蛋白，因此寻找了一种防止无意中摄取的机制。靶细胞上的CD47(整合素相关蛋白)和吞噬细胞上的高度糖基化的跨膜蛋白SIRPα(SHPS-1)之间的相互作用的中断，允许活细胞以钙网蛋白/LRP依赖的方式摄取。在凋亡细胞上，CD47被改变和/或丢失，不再激活SIRPα。凋亡细胞上的这些变化创造了一个环境，在这个环境中，“不要吃我”的信号变得不活跃，而“吃我”的信号，包括钙网蛋白和磷脂酰丝氨酸，聚集在一起，发出移除的信号。
Apoptotic-cell removal is critical for development, tissue homeostasis, and resolution of inflammation. Although many candidate systems exist, only phosphatidylserine has been identified as a general recognition ligand on apoptotic cells. We demonstrate here that calreticulin acts as a second general recognition ligand by binding and activating LDL-receptor-related protein (LRP) on the engulfing cell. Since surface calreticulin is also found on viable cells, a mechanism preventing inadvertent uptake was sought. Disruption of interactions between CD47 (integrin-associated protein) on the target cell and SIRP alpha (SHPS-1), a heavily glycosylated transmembrane protein on the engulfing cell, permitted uptake of viable cells in a calreticulin/LRP-dependent manner. On apoptotic cells, CD47 was altered and/or lost and no longer activated SIRP alpha. These changes on the apoptotic cell create an environment where "don't eat me" signals are rendered inactive and "eat me" signals, including calreticulin and phosphatidylserine, congregate together and signal for removal.