Phospholipid flippase ATP11C is endocytosed and downregulated following Ca(2+)-mediated protein kinase C activation.
Phospholipid flippase ATP11C is endocytosed and downregulated following Ca(2+)-mediated protein kinase C activation.
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DOI：
10.1038/s41467-017-01338-1
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发表时间：
2017-11-10
影响因子：
16.6
通讯作者：
Shin HW
中科院分区：
文献类型：
--
作者：
Takatsu H;Takayama M;Naito T;Takada N;Tsumagari K;Ishihama Y;Nakayama K;Shin HW
我们和其他人发现，ATP 11 A和ATP 11 C，P4-ATP酶家族的成员，将磷脂酰丝氨酸（PS）和磷脂酰乙醇胺从细胞外质转运到质膜上的细胞质小叶。PS暴露于活化的血小板、红细胞和凋亡细胞的质膜外叶上，这需要抑制PS翻转酶以及激活乱序酶。虽然ATP 11 A和ATP 11 C在凋亡细胞中被半胱天冬酶切割，但仍不清楚PS翻转酶活性在非凋亡细胞中是如何调节的。在这里，我们报告的PS-翻转酶ATP 11 C，而不是ATP 11 A，是螯合从质膜通过网格蛋白介导的内吞作用后，钙离子介导的PKC激活。重要的是，我们发现，一个特征性的双亮氨酸基序（SVRPLL）在C-末端胞质区域的ATP 11 C成为PKC激活后的功能。此外，ATP 11 C的内吞作用是由经由Gq偶联受体的Ca 2+信号传导诱导的。我们的数据提供了哺乳动物P4-ATP酶的信号依赖性调节的第一个证据。ATP 11 C是一种翻转酶，其利用ATP水解将磷脂转运到质膜上。在这里，作者表明，激活钙离子依赖性蛋白激酶C增加ATP 11 C的内吞作用，从而下调磷脂易位。
We and others showed that ATP11A and ATP11C, members of the P4-ATPase family, translocate phosphatidylserine (PS) and phosphatidylethanolamine from the exoplasmic to the cytoplasmic leaflets at the plasma membrane. PS exposure on the outer leaflet of the plasma membrane in activated platelets, erythrocytes, and apoptotic cells was proposed to require the inhibition of PS-flippases, as well as activation of scramblases. Although ATP11A and ATP11C are cleaved by caspases in apoptotic cells, it remains unclear how PS-flippase activity is regulated in non-apoptotic cells. Here we report that the PS-flippase ATP11C, but not ATP11A, is sequestered from the plasma membrane via clathrin-mediated endocytosis upon Ca2+-mediated PKC activation. Importantly, we show that a characteristic di-leucine motif (SVRPLL) in the C-terminal cytoplasmic region of ATP11C becomes functional upon PKC activation. Moreover endocytosis of ATP11C is induced by Ca2+-signaling via Gq-coupled receptors. Our data provide the first evidence for signal-dependent regulation of mammalian P4-ATPase. ATP11C is a flippase that uses ATP hydrolysis to translocate phospholipids at the plasma membrane. Here, the authors show that the activation of Ca2+-dependent protein kinase C increases ATP11C endocytosis thus downregulating phospholipid translocation.
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DOI：
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发表时间：
2016-07
期刊：
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发表时间：
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期刊：
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