背景:血小板中的Kindlin-3在支持整合素αIIbβ3活化中起重要作用,血小板扩散,聚合,和凝块通过与整联蛋白β3细胞质尾结合而缩回。然而,kindlin-3介导血小板中整合素αIIbβ3与肌球蛋白串扰的机制尚不清楚。
目的:研究Myl6在支持血小板中整合素αIIbβ3活化中的作用。
方法:Myl6fl/flPF4-Cre小鼠,巨核细胞谱系缺乏Myl6,产生了,并分析了Myl6缺陷型血小板中整合素αIIbβ3的激活。
结果:我们鉴定了一种新的kindlin-3结合蛋白,Myl6,血小板中肌球蛋白的必需轻链。Myl6fl/flPF4-Cre小鼠表现出由前血小板形成缺陷引起的显著大血小板减少症。在没有Myl6的情况下,血小板中整合素αIIbβ3的激活被显著抑制,血小板聚集明显受损。有趣的是,与单价配体相比,血小板中Myl6的缺乏优先影响多价配体与整合素αIIbβ3的活化结合,表明Myl6可能通过与kindlin-3结合而有助于整合素αIIbβ3的亲合力调节。此外,Myl6fl/flPF4-Cre小鼠的凝血能力受损,并且始终如一,这些小鼠表现出止血和血栓形成功能的缺陷。
结论:总之,这些结果表明,Myl6作为一种新型的kindlin-3结合伴侣,需要支持血小板中整合素αIIbβ3的活化,在止血和血栓形成中起重要作用。
BACKGROUND: Kindlin-3 in platelets plays an essential role in supporting integrin αIIbβ3 activation, platelet spreading, aggregation, and clot retraction by binding to the integrin β3 cytoplasmic tail. However, the mechanism by which kindlin-3 mediates the crosstalk between integrin αIIbβ3 and myosin in platelets remains unknown.
OBJECTIVE: To examine the role of myosin light chain 6 (Myl6) in supporting integrin αIIbβ3 activation in platelets.
METHODS: Myl6fl/flPF4-Cre mice with a deficiency of Myl6 in the megakaryocyte lineage were generated, and integrin αIIbβ3 activation in Myl6-deficient platelets was analyzed.
RESULTS: We identified a novel kindlin-3 binding protein, Myl6, an essential light chain of myosin in platelets. Myl6fl/flPF4-Cre mice exhibited significant macrothrombocytopenia resulting from defective proplatelet formation. In the absence of Myl6, integrin αIIbβ3 activation in platelets was significantly suppressed, and platelet aggregation was substantially impaired. Interestingly, the deficiency of Myl6 in platelets preferentially affected the binding of a multivalent ligand compared to a monovalent ligand to integrin αIIbβ3 upon activation, indicating that Myl6 may contribute to the avidity modulation of integrin αIIbβ3 by binding to kindlin-3. Furthermore, blood coagulation ability was impaired in Myl6fl/flPF4-Cre mice, and consistently, these mice exhibited defects in both hemostatic and thrombotic functions.
CONCLUSIONS: In summary, these results suggest that Myl6, as a novel kindlin-3 binding partner, is required to support integrin αIIbβ3 activation in platelets, which plays an important role in both hemostasis and thrombosis.