Essential role of zyxin in platelet biogenesis and glycoprotein Ib-IX surface expression.
Essential role of zyxin in platelet biogenesis and glycoprotein Ib-IX surface expression.
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zyxin 在血小板生物发生和糖蛋白 Ib-IX 表面表达中的重要作用
DOI：
10.1038/s41419-021-04246-x
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发表时间：
2021-10-16
影响因子：
9
通讯作者：
Dai K
中科院分区：
文献类型：
--
作者：
Yan R;Ge X;Pang N;Ye H;Yuan L;Cheng B;Zhou K;Yang M;Sun Y;Zhang S;Ding Z;Luo J;Ruan C;Dai K
血小板由巨核细胞（MK）的细胞质通过肌动蛋白细胞骨架重组产生。Zyxin是一种黏着斑蛋白，在真核生物中广泛表达，调节肌动蛋白的重塑。Zyxin在巨核细胞分化过程中上调，然而，zyxin在血小板生成中的作用尚不清楚。在这里，我们表明，zyxin消融导致严重的巨血小板减少症。血小板寿命和血小板生成素水平之间的野生型和zyxin缺陷的小鼠，但MK成熟，分界膜系统的形成，和前血小板生成明显受损zyxin的情况下。与巨血小板减少症相关的蛋白质的差异蛋白质组学分析显示，糖蛋白（GP）Ib-IX显着减少zyxin缺乏血小板。此外，GPIb-IX表面水平降低zyxin缺陷的MK。在人巨核细胞系中，zyxin的敲低导致GPIbα被溶酶体降解，导致GPIb-IX表面水平降低。我们进一步发现，zyxin与血管舒张刺激磷蛋白（VASP）共定位，zyxin的丢失导致VASP和肌动蛋白细胞骨架在血小板和MK中的弥散分布。在zyxin缺陷的造血祖细胞衍生的MK中用VASP结合位点重建zyxin恢复GPIb-IX表面表达和前血小板生成。总之，我们的研究结果确定zyxin作为血小板生物合成和GPIb-IX表面表达的调节剂，通过VASP介导的细胞骨架重组，这表明可能的发病机制macroplateletia。
Platelets are generated from the cytoplasm of megakaryocytes (MKs) via actin cytoskeleton reorganization. Zyxin is a focal adhesion protein and wildly expressed in eukaryotes to regulate actin remodeling. Zyxin is upregulated during megakaryocytic differentiation; however, the role of zyxin in thrombopoiesis is unknown. Here we show that zyxin ablation results in profound macrothrombocytopenia. Platelet lifespan and thrombopoietin level were comparable between wild-type and zyxin-deficient mice, but MK maturation, demarcation membrane system formation, and proplatelet generation were obviously impaired in the absence of zyxin. Differential proteomic analysis of proteins associated with macrothrombocytopenia revealed that glycoprotein (GP) Ib-IX was significantly reduced in zyxin-deficient platelets. Moreover, GPIb-IX surface level was decreased in zyxin-deficient MKs. Knockdown of zyxin in a human megakaryocytic cell line resulted in GPIbα degradation by lysosomes leading to the reduction of GPIb-IX surface level. We further found that zyxin was colocalized with vasodilator-stimulated phosphoprotein (VASP), and loss of zyxin caused diffuse distribution of VASP and actin cytoskeleton disorganization in both platelets and MKs. Reconstitution of zyxin with VASP binding site in zyxin-deficient hematopoietic progenitor cell-derived MKs restored GPIb-IX surface expression and proplatelet generation. Taken together, our findings identify zyxin as a regulator of platelet biogenesis and GPIb-IX surface expression through VASP-mediated cytoskeleton reorganization, suggesting possible pathogenesis of macrothrombocytopenia.
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DOI：
10.1083/jcb.201304054
发表时间：
2013-06-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Machlus KR;Italiano JE Jr
通讯作者：
Italiano JE Jr
影响因子：
20.3
作者：
Estevez, Brian;Kim, Kyungho;Du, Xiaoping
通讯作者：
Du, Xiaoping
影响因子：
4.8
作者：
Drees, B;Friederich, E;Grolsteyn, RM
通讯作者：
Grolsteyn, RM
影响因子：
4.8
作者：
Bachmann, C;Fischer, L;Reinhard, M
通讯作者：
Reinhard, M
影响因子：
7.5
作者：
Lanzetti, Letizia
通讯作者：
Lanzetti, Letizia