Solarz Jean, Soukaseum Christelle, Frémont Stéphane, Eymieux Sébastien, Nabli Camilia, Repérant Christelle, Rossi Elisa, Bordet Jean-Claude, Denis Cécile V, Mangin Pierre, Boulaftali Yacine, Pasterkamp R Jeroen, Raslova Hana, Baruch Dominique, Adam Frédéric, Echard Arnaud, Kauskot Alexandre
HITh, UMR_S1176, INSERM, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
Institut Pasteur, Université Paris Cité, CNRS UMR3691, Paris, France.
Nat Commun. 2025 Aug 10;16(1):7375. doi: 10.1038/s41467-025-62487-2.
Mechano-dependent interactions are key to thrombus formation and hemostasis, enabling stable platelet adhesion to injured vessels. The interaction between von Willebrand factor (VWF) and the platelet receptor GPIb-IX-V is central to this process. While GPIbα connects to the actin cytoskeleton, whether actin dynamics are important for GPIbα function under hemodynamic, high shear conditions remains largely unknown. Here, we show that actin disassembly is critical for proper VWF-GPIbα binding under shear. Mechanistically, we identify the oxidoreductase MICAL1 as a shear-activated regulator that promotes local F-actin disassembly around the GPIb-IX-V complex. This enables its translocation to lipid rafts and reinforces VWF binding. MICAL1-deficient platelets display impaired adhesion, increased deformability under shear, and defective thrombus formation in vivo. Thus, MICAL1 drives shear-dependent actin remodeling that supports GPIb-IX-V mechanotransduction and platelet function. These findings uncover a role for actin oxidation in platelet adhesion, providing a connection between cytoskeletal redox control and platelet function during thrombus formation.
机械力依赖的相互作用是血栓形成和止血的关键，可使血小板稳定黏附于受损血管。血管性血友病因子（VWF）与血小板受体糖蛋白Ib-IX-V之间的相互作用是这一过程的核心。虽然糖蛋白Ibα连接到肌动蛋白细胞骨架，但在血流动力学、高剪切条件下肌动蛋白动力学对糖蛋白Ibα功能是否重要仍 largely未知。在此，我们表明肌动蛋白解聚对于剪切力作用下VWF与糖蛋白Ibα的正确结合至关重要。从机制上讲，我们确定氧化还原酶MICAL1是一种剪切激活调节因子，可促进糖蛋白Ib-IX-V复合物周围局部F-肌动蛋白解聚。这使其易位至脂筏并增强VWF结合。缺乏MICAL1的血小板黏附受损，在剪切力作用下变形性增加，且在体内血栓形成存在缺陷。因此，MICAL1驱动剪切力依赖的肌动蛋白重塑，支持糖蛋白Ib-IX-V机械转导和血小板功能。这些发现揭示了肌动蛋白氧化在血小板黏附中的作用，为血栓形成过程中细胞骨架氧化还原控制与血小板功能之间建立了联系。
