Essential role of zyxin in platelet biogenesis and glycoprotein Ib-IX surface expression
| Autor: | Xinxin Ge, Kangxi Zhou, Liuxia Yuan, Yueyue Sun, Su-Qin Zhang, Zhongren Ding, Bin Cheng, Mengnan Yang, Changgeng Ruan, Rong Yan, Ningbo Pang, Kesheng Dai, Jincai Luo, Honglei Ye |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Proteomics Cancer Research Microtubules Zyxin Mice Bone Marrow Thrombopoiesis Cytoskeleton biology Disease genetics Chemistry Microfilament Proteins Thrombin Cell Differentiation Cell biology Actin Cytoskeleton Platelet Glycoprotein GPIb-IX Complex Female Megakaryocytes Protein Binding Blood Platelets Immunology macromolecular substances Article Cell Line Focal adhesion Cellular and Molecular Neuroscience Animals Humans RNA Messenger QH573-671 Platelet Count Cell Membrane Actin cytoskeleton reorganization Fibrinogen Actin remodeling Cell Biology Phosphoproteins Actin cytoskeleton Thrombocytopenia Mice Inbred C57BL Glycoprotein Ib Proteolysis biology.protein Mutant Proteins Lysosomes Cytology Cell Adhesion Molecules |
| Zdroj: | Cell Death and Disease, Vol 12, Iss 11, Pp 1-13 (2021) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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