Calpain cleaves phospholipid flippase ATP8A1 during apoptosis in platelets
Calpain cleaves phospholipid flippase ATP8A1 during apoptosis in platelets
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DOI：
10.1182/bloodadvances.2018023473
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发表时间：
2019-02-12
期刊：
影响因子：
7.5
通讯作者：
Broer, Stefan
中科院分区：
文献类型：
--
作者：
Jing, Weidong;Yabas, Mehmet;Broer, Stefan
磷脂在血浆/细胞器膜中的不对称分布是通过静息细胞中的磷脂翻转酶产生和维持的，但在凋亡细胞和活化血小板中被破坏，导致细胞表面的磷脂酰丝氨酸（PS）暴露。在凋亡过程中稳定的PS暴露需要翻转酶的失活以防止PS被再内化。在这里，我们表明，翻转酶ATP 8A 1是高度表达在小鼠和人类血小板，但不存在于质膜。ATP 8A 1在细胞凋亡期间被半胱氨酸蛋白酶钙蛋白酶切割，并且通过半胱天冬酶抑制间接阻止切割，包括阻断钙流入血小板和随后的钙蛋白酶激活。相比之下，在用凝血酶和胶原活化并暴露PS的血小板中，ATP 8A 1保持完整。这些数据揭示了一种新的翻转酶切割机制，并表明翻转酶活性在细胞内膜不同血小板经历凋亡和活化。
The asymmetric distribution of phospholipids in the plasma/organellar membranes is generated and maintained through phospholipid flippases in resting cells, but becomes disrupted in apoptotic cells and activated platelets, resulting in phosphatidylserine (PS) exposure on the cell surface. Stable PS exposure during apoptosis requires inactivation of flippases to prevent PS from being reinternalized. Here we show that flippase ATP8A1 is highly expressed in both murine and human platelets, but is not present in the plasma membrane. ATP8A1 is cleaved by the cysteine protease calpain during apoptosis, and the cleavage is prevented indirectly by caspase inhibition, involving blockage of calcium influx into platelets and subsequent calpain activation. In contrast, in platelets activated with thrombin and collagen and exposing PS, ATP8A1 remains intact. These data reveal a novel mechanism of flippase cleavage and suggest that flippase activity in intracellular membranes differs between platelets undergoing apoptosis and activation.