Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure
Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure
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DOI：
10.1126/science.1252809
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发表时间：
2014-06-06
期刊：
影响因子：
56.9
通讯作者：
Nagata, Shigekazu
中科院分区：
文献类型：
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作者：
Segawa, Katsumori;Kurata, Sachiko;Nagata, Shigekazu
磷脂在质膜上呈不对称分布。这种不对称分布在细胞凋亡过程中被破坏，暴露在细胞表面的磷脂酰丝氨酸（PtdSer）。在人类细胞中使用单倍体遗传筛选，我们发现ATP 11 C（腺苷三磷酸酶类型11 C）和CDC 50 A（细胞分裂周期蛋白50 A）是氨基磷脂从外质膜小叶易位到内质膜小叶所必需的;也就是说，它们显示翻转酶活性。ATP 11 C含有半胱天冬酶识别位点，在这些位点的突变产生半胱天冬酶抗性ATP 11 C，而不影响其翻转酶活性。细胞表达半胱天冬酶耐药ATP 11 C没有暴露PtdSer在凋亡过程中，并没有被吞噬的巨噬细胞，这表明，翻转酶活性的失活所需的凋亡PtdSer曝光。CDC 50 A缺陷细胞在其表面上显示PtdSer，并被巨噬细胞吞噬，表明PtdSer足以作为“吃我”信号。
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.