2. Academic Validation
  3. 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

  • Cell Death Dis. 2021 Oct 16;12(11):955. doi: 10.1038/s41419-021-04246-x.
Rong Yan  # 1,  Xinxin Ge  # 1,  Ningbo Pang  # 1,  Honglei Ye 1,  Liuxia Yuan 1,  Bin Cheng 1,  Kangxi Zhou 1,  Mengnan Yang 1,  Yueyue Sun 1,  Suqin Zhang 1,  Zhongren Ding 2,  Jincai Luo 3,  Changgeng Ruan 1,  Kesheng Dai 4
Affiliations

Affiliations

  • 1 Jiangsu Institute of Hematology, Cyrus Tang Medical Institute, The First Affiliated Hospital and Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, National Clinical Research Center for Hematological Diseases, Suzhou, 215006, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
  • 3 Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China.
  • 4 Jiangsu Institute of Hematology, Cyrus Tang Medical Institute, The First Affiliated Hospital and Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, National Clinical Research Center for Hematological Diseases, Suzhou, 215006, China. kdai@suda.edu.cn.
  • # Contributed equally.
PMID: 34657146 DOI: 10.1038/s41419-021-04246-x
Abstract

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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