Migfilin supports hemostasis and thrombosis through regulating platelet αIIbβ3 outside-in signaling.
Migfilin supports hemostasis and thrombosis through regulating platelet αIIbβ3 outside-in signaling.
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Migfilin 通过调节血小板 αIIbbeta3 由外向内信号传导来支持止血和血栓形成。
DOI：
10.3324/haematol.2019.232488
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发表时间：
2020-11-01
期刊：
影响因子：
10.1
通讯作者：
Hu H
中科院分区：
文献类型：
--
作者：
Zhou Y;Hu M;Chen X;Wang S;Li J;Sa L;Li L;Huang J;Cheng H;Hu H
阐明整合素aIIbβ3的调控机制是理解血小板生物学和血栓性疾病的关键。先前的体外研究表明，migfilin在支持血小板aIIbβ3活化中发挥作用，然而，migfilin对体内血栓形成和止血的作用以及migfilin在血小板中的详细机制尚不清楚。在这项研究中，通过migfilin基因敲除（migfilin-/-）小鼠，我们报告说，migfilin是一个关键的止血和血栓形成的正调控因子。在FeCl 3诱导的肠系膜小动脉血栓形成中，Migfilin-/-小鼠的尾部出血时间几乎增加了一倍，闭塞时间延长。移行因子缺乏阻碍胶原蛋白表面的血小板血栓形成，并损害血小板聚集和致密颗粒分泌。在aIIbβ3双向信号传导过程中，由特征性功能读数和独特信号传导分子的磷酸化状态支持，migfilin-/-血小板的功能缺陷似乎与受损的由外向内信号传导机制相关，而不是由内向外信号传导机制。一种合成的细胞可渗透的migfilin肽，含有细丝蛋白A结合序列，挽救了migfilin-/-血小板信号分子的功能缺陷和磷酸化。最后，migfilin不影响静息血小板中细丝蛋白A与aIIbβ3的β3亚基的结合，但在外向-内向信号传导过程中阻碍细丝蛋白A与β3的重新结合，提示migfilin通过调节血小板中aIIbβ3与细丝蛋白A的相互作用动力学发挥作用。我们的研究增强了目前对血小板整合素aIIbβ3介导的由外向内信号传导的理解，并证明migfilin是血小板活化、止血和血栓形成的重要调节剂。
Elucidating the regulation mechanism of integrin aIIbβ3 is key to understanding platelet biology and thrombotic diseases. Previous in vitro studies have implicated a role of migfilin in the support of platelet aIIbβ3 activation, however, contribution of migfilin to thrombosis and hemostasis in vivo and a detailed mechanism of migfilin in platelets are not known. In this study, through migfilin knock-out (migfilin-/-) mice, we report that migfilin is a pivotal positive regulator of hemostasis and thrombosis. Migfilin-/- mice show a nearly doubled tail-bleeding time and a prolonged occlusion time in FeCl3-induced mesenteric arteriolar thrombosis. Migfilin deficiency impedes platelet thrombi formation on a collagen surface and impairs platelet aggregation and dense-granule secretion. Supported by characteristic functional readings and the phosphorylation status of distinctive signaling molecules in the bidirectional signaling processes of aIIbβ3, the functional defects of migfilin-/- platelets appear to be mechanistically associated with a compromised outside-in signaling, rather than inside-out signaling. A synthesized cell-permeable migfilin peptide harboring filamin A binding sequence rescued the defective function and phosphorylation of signaling molecules of migfilin-/- platelets. Finally, migfilin does not influence the binding of filamin A and β3 subunit of aIIbβ3 in resting platelets, but hampers the re-association of filamin A and β3 during the conduct of outside- in signaling, suggesting that migfilin functions through regulating the interaction dynamics of aIIbβ3 and filamin A in platelets. Our study enhances the current understanding of platelet integrin aIIbβ3-mediated outside-in signaling and proves that migfilin is an important regulator for platelet activation, hemostasis and thrombosis.