Gardai Shyra J, McPhillips Kathleen A, Frasch S Courtney, Janssen William J, Starefeldt Anna, Murphy-Ullrich Joanne E, Bratton Donna L, Oldenborg Per-Arne, Michalak Marek, Henson Peter M
Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St., Denver, Colorado 80206, USA.
Cell. 2005 Oct 21;123(2):321-34. doi: 10.1016/j.cell.2005.08.032.
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 SIRPalpha (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 SIRPalpha. 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.
凋亡细胞的清除对于发育、组织稳态以及炎症的消退至关重要。尽管存在许多候选系统，但只有磷脂酰丝氨酸已被确定为凋亡细胞上的一种通用识别配体。我们在此证明，钙网蛋白通过结合并激活吞噬细胞上的低密度脂蛋白受体相关蛋白（LRP），作为第二种通用识别配体发挥作用。由于在活细胞表面也发现了钙网蛋白，因此人们寻找一种防止意外摄取的机制。靶细胞上的CD47（整合素相关蛋白）与吞噬细胞上的一种高度糖基化跨膜蛋白信号调节蛋白α（SIRPα，又称SHPS-1）之间相互作用的破坏，使得活细胞能够以钙网蛋白/LRP依赖的方式被摄取。在凋亡细胞上，CD47发生改变和/或丢失，不再激活SIRPα。凋亡细胞上的这些变化创造了一种环境，即“别吃我”信号失活，而包括钙网蛋白和磷脂酰丝氨酸在内的“吃我”信号聚集在一起并发出清除信号。
