Immune thrombocytopenia (ITP) is a complicated bleeding disease characterized by a sharp platelet reduction. As a dominating element involved in ITP, megakaryocytes (MKs) are responsible for thrombopoiesis. However, the mechanism underlying the dysregulation of thrombopoiesis that occurs in ITP remains unidentified. In this study, we examined the role of Yes-associated protein 1 (YAP1) in thrombopoiesis during ITP. We observed reduced YAP1 expression with cytoskeletal actin misalignment in MKs from patients with ITP. Using an experimental ITP mouse model, we showed that reduced YAP1 expression induced aberrant MK distribution, reduced the percentage of late MKs among the total MKs, and caused submaximal platelet recovery. Mechanistically, YAP1 upregulation by binding of GATA-binding protein 1 to its promoter promoted MK maturation. Phosphorylated YAP1 promoted cytoskeletal activation by binding its WW2 domain to myosin heavy chain 9, thereby facilitating thrombopoiesis. Targeting YAP1 with its activator XMU-MP-1 was sufficient to rescue cytoskeletal defects and thrombopoiesis dysregulation in YAP1+/− mice with ITP and patients. Taken together, these results demonstrate the crucial role of YAP1 in thrombopoiesis, providing potential for the development of diagnostic markers and therapeutic options for ITP.

中文翻译：

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YAP1 通过与免疫性血小板减少症中的 MYH9 结合来调节血小板生成


免疫性血小板减少症 （ITP） 是一种复杂的出血性疾病，其特征是血小板急剧减少。作为参与 ITP 的显性元件，巨核细胞 （MKs） 负责血小板生成。然而，ITP 中发生的血小板生成失调的潜在机制仍未确定。在这项研究中，我们检查了 Yes 相关蛋白 1 （YAP1） 在 ITP 期间血小板生成中的作用。我们观察到 ITP 患者 MK 中 YAP1 表达降低，细胞骨架肌动蛋白错位。使用实验 ITP 小鼠模型，我们表明 YAP1 表达降低诱导异常的 MK 分布，降低晚期 MKs 在总 MK 中的百分比，并导致次最大值血小板回收。从机制上讲，通过将 GATA 结合蛋白 1 与其启动子结合来上调 YAP1 促进了 MK 成熟。磷酸化 YAP1 通过将其 WW2 结构域与肌球蛋白重链 9 结合来促进细胞骨架活化，从而促进血小板生成。用激活剂 XMU-MP-1 靶向 YAP1 足以挽救 YAP1 + /− ITP 小鼠和患者的细胞骨架缺陷和血小板生成失调。综上所述，这些结果证明了 YAP1 在血小板生成中的关键作用，为 ITP 诊断标志物和治疗选择的开发提供了潜力。