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Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis

Author

Listed:
  • Keyu Lv

    (Huazhong University of Science and Technology)

  • Shuai Chen

    (Huazhong University of Science and Technology
    Guizhou University of Traditional Chinese Medicine)

  • Xulin Xu

    (Huazhong University of Science and Technology
    The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province
    Huazhong University of Science and Technology)

  • Joyce Chiu

    (University of Sydney)

  • Haoqing J. Wang

    (The University of Sydney
    The University of Sydney)

  • Yunyun Han

    (Huazhong University of Science and Technology)

  • Xiaodan Yang

    (Huazhong University of Science and Technology)

  • Sheryl R. Bowley

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Hao Wang

    (Huazhong University of Science and Technology)

  • Zhaoming Tang

    (Huazhong University of Science and Technology)

  • Ning Tang

    (Huazhong University of Science and Technology)

  • Aizhen Yang

    (Soochow University)

  • Shuofei Yang

    (Shanghai Jiao Tong University)

  • Jinyu Wang

    (Huazhong University of Science and Technology, and the Key Laboratory of Oral and Maxillofacial Development and Regeneration of Hubei Province)

  • Si Jin

    (Huazhong University of Science and Technology)

  • Yi Wu

    (Soochow University)

  • Alvin H. Schmaier

    (University Hospitals Cleveland Medical Center and Case Western Reserve University)

  • Lining A. Ju

    (The University of Sydney
    The University of Sydney)

  • Philip J. Hogg

    (University of Sydney)

  • Chao Fang

    (Huazhong University of Science and Technology
    The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province
    Huazhong University of Science and Technology)

Abstract

The essence of difference between hemostasis and thrombosis is that the clotting reaction is a highly fine-tuned process. Vascular protein disulfide isomerase (PDI) represents a critical mechanism regulating the functions of hemostatic proteins. Herein we show that histidine-rich glycoprotein (HRG) is a substrate of PDI. Reduction of HRG by PDI enhances the procoagulant and anticoagulant activities of HRG by neutralization of endothelial heparan sulfate (HS) and inhibition of factor XII (FXIIa) activity, respectively. Murine HRG deficiency (Hrg−/−) leads to delayed onset but enhanced formation of thrombus compared to WT. However, in the combined FXII deficiency (F12−/−) and HRG deficiency (by siRNA or Hrg−/−), there is further thrombosis reduction compared to F12−/− alone, confirming HRG’s procoagulant activity independent of FXIIa. Mutation of target disulfides of PDI leads to a gain-of-function mutant of HRG that promotes its activities during coagulation. Thus, PDI-HRG pathway fine-tunes thrombosis by promoting its rapid initiation via neutralization of HS and preventing excessive propagation via inhibition of FXIIa.

Suggested Citation

  • Keyu Lv & Shuai Chen & Xulin Xu & Joyce Chiu & Haoqing J. Wang & Yunyun Han & Xiaodan Yang & Sheryl R. Bowley & Hao Wang & Zhaoming Tang & Ning Tang & Aizhen Yang & Shuofei Yang & Jinyu Wang & Si Jin , 2024. "Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47493-0
    DOI: 10.1038/s41467-024-47493-0
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    References listed on IDEAS

    as
    1. Sheryl R. Bowley & Chao Fang & Glenn Merrill-Skoloff & Barbara C. Furie & Bruce Furie, 2017. "Protein disulfide isomerase secretion following vascular injury initiates a regulatory pathway for thrombus formation," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    2. Roelof H. Bekendam & Pavan K. Bendapudi & Lin Lin & Partha P. Nag & Jun Pu & Daniel R. Kennedy & Alexandra Feldenzer & Joyce Chiu & Kristina M. Cook & Bruce Furie & Mingdong Huang & Philip J. Hogg & R, 2016. "A substrate-driven allosteric switch that enhances PDI catalytic activity," Nature Communications, Nature, vol. 7(1), pages 1-11, November.
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