2. Academic Validation
  3. Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis

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

  • Nat Commun. 2024 Apr 11;15(1):3129. doi: 10.1038/s41467-024-47493-0.
Keyu Lv # 1,  Shuai Chen # 1 2,  Xulin Xu # 1 3 4,  Joyce Chiu 5,  Haoqing J Wang 6 7,  Yunyun Han 8,  Xiaodan Yang 8,  Sheryl R Bowley 9,  Hao Wang 1,  Zhaoming Tang 10,  Ning Tang 11,  Aizhen Yang 12,  Shuofei Yang 13,  Jinyu Wang 14,  Si Jin 15,  Yi Wu 12,  Alvin H Schmaier 16,  Lining A Ju 6 7,  Philip J Hogg 5,  Chao Fang 17 18 19
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
  • 2 Department of Pharmacology, School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China.
  • 3 The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China.
  • 4 Tongji-Rongcheng Center for Biomedicine, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
  • 5 The Centenary Institute, University of Sydney, Sydney, NSW, 2006, Australia.
  • 6 School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, Darlington, NSW, 2008, Australia.
  • 7 The University of Sydney Nano Institute (Sydney Nano), The University of Sydney, Camperdown, NSW, 2006, Australia.
  • 8 Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
  • 9 Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
  • 10 Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
  • 11 Department of Clinical Laboratory, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
  • 12 The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China.
  • 13 Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 14 School of Stomatology, Tongji Medical Collage, Huazhong University of Science and Technology, and the Key Laboratory of Oral and Maxillofacial Development and Regeneration of Hubei Province, Wuhan, 430030, Hubei, China.
  • 15 Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
  • 16 Department of Medicine, Hematology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, 44106, USA.
  • 17 Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. fangc@hust.edu.cn.
  • 18 The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China. fangc@hust.edu.cn.
  • 19 Tongji-Rongcheng Center for Biomedicine, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. fangc@hust.edu.cn.
  • # Contributed equally.
PMID: 38605050 DOI: 10.1038/s41467-024-47493-0
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.

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