Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
Nat Commun. 2017 Nov 10;8(1):1423. doi: 10.1038/s41467-017-01338-1.
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 Ca-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 Ca-signaling via Gq-coupled receptors. Our data provide the first evidence for signal-dependent regulation of mammalian P4-ATPase.
我们和其他人的研究表明，P4-ATPase 家族的成员 ATP11A 和 ATP11C 可将磷脂酰丝氨酸（PS）和磷脂酰乙醇胺从质膜的胞外小叶转运到细胞质小叶。在激活的血小板、红细胞和凋亡细胞中，质膜外小叶上 PS 的暴露被认为需要 PS 翻转酶的抑制以及 scramblase 的激活。尽管在凋亡细胞中 caspase 可切割 ATP11A 和 ATP11C，但尚不清楚非凋亡细胞中 PS 翻转酶活性是如何调节的。在这里，我们报告说，在 Ca 介导的 PKC 激活时，PS 翻转酶 ATP11C 而非 ATP11A 通过网格蛋白介导的内吞作用从质膜上隔离出来。重要的是，我们表明，ATP11C 细胞质 C 末端的特征二亮氨酸基序（SVRPLL）在 PKC 激活时变得具有功能。此外，通过 Gq 偶联受体的 Ca 信号诱导 ATP11C 的内吞作用。我们的数据为哺乳动物 P4-ATPase 的信号依赖性调节提供了第一个证据。
