Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Kyoto 606-8501, Japan.
Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.
Science. 2014 Jun 6;344(6188):1164-8. doi: 10.1126/science.1252809.
Phospholipids are asymmetrically distributed in the plasma membrane. This asymmetrical distribution is disrupted during apoptosis, exposing phosphatidylserine (PtdSer) on the cell surface. Using a haploid genetic screen in human cells, we found that ATP11C (adenosine triphosphatase type 11C) and CDC50A (cell division cycle protein 50A) are required for aminophospholipid translocation from the outer to the inner plasma membrane leaflet; that is, they display flippase activity. ATP11C contained caspase recognition sites, and mutations at these sites generated caspase-resistant ATP11C without affecting its flippase activity. Cells expressing caspase-resistant ATP11C did not expose PtdSer during apoptosis and were not engulfed by macrophages, which suggests that inactivation of the flippase activity is required for apoptotic PtdSer exposure. CDC50A-deficient cells displayed PtdSer on their surface and were engulfed by macrophages, indicating that PtdSer is sufficient as an "eat me" signal.
磷脂在质膜中呈不对称分布。这种不对称分布在细胞凋亡过程中被破坏，导致磷脂酰丝氨酸（PtdSer）暴露在细胞表面。通过人类细胞的单倍体遗传筛选，我们发现 ATP11C（三磷酸腺苷酶 11C）和 CDC50A（细胞分裂周期蛋白 50A）是从质膜外层向内层小叶转移氨基磷脂所必需的；也就是说，它们具有翻转酶活性。ATP11C 包含半胱天冬酶识别位点，这些位点的突变生成对半胱天冬酶有抗性的 ATP11C，而不影响其翻转酶活性。表达对半胱天冬酶有抗性的 ATP11C 的细胞在细胞凋亡过程中不暴露 PtdSer，也不会被巨噬细胞吞噬，这表明翻转酶活性的失活是细胞凋亡时 PtdSer 暴露所必需的。CDC50A 缺陷细胞表面呈现 PtdSer，并被巨噬细胞吞噬，表明 PtdSer 足以作为“吃我”信号。
