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

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, Yi Wu, Alvin H. Schmaier, Lining A. Ju, Philip J. Hogg and Chao Fang ()
Additional contact information
Keyu Lv: Huazhong University of Science and Technology
Shuai Chen: Huazhong University of Science and Technology
Xulin Xu: Huazhong University of Science and Technology
Joyce Chiu: University of Sydney
Haoqing J. Wang: 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
Philip J. Hogg: University of Sydney
Chao Fang: Huazhong University of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47493-0

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