Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis
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 glycoprote...
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| Format: | Article |
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Nature Portfolio
2024-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-47493-0 |
| _version_ | 1797209182362927104 |
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| author | 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 Chao Fang |
| author_facet | 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 Chao Fang |
| author_sort | Keyu Lv |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T09:50:38Z |
| format | Article |
| id | doaj.art-0c086c6b87a448a69a22678f0a155a5d |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T09:50:38Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-0c086c6b87a448a69a22678f0a155a5d2024-04-14T11:21:11ZengNature PortfolioNature Communications2041-17232024-04-0115111910.1038/s41467-024-47493-0Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosisKeyu Lv0Shuai Chen1Xulin Xu2Joyce Chiu3Haoqing J. Wang4Yunyun Han5Xiaodan Yang6Sheryl R. Bowley7Hao Wang8Zhaoming Tang9Ning Tang10Aizhen Yang11Shuofei Yang12Jinyu Wang13Si Jin14Yi Wu15Alvin H. Schmaier16Lining A. Ju17Philip J. Hogg18Chao Fang19Department 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 TechnologyDepartment 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 TechnologyDepartment 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 TechnologyThe Centenary Institute, University of SydneySchool of Biomedical Engineering, Faculty of Engineering, The University of SydneyDepartment of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDivision of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment 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 TechnologyDepartment of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Clinical Laboratory, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyThe Cyrus Tang Hematology Center, Soochow UniversityDepartment of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversitySchool of Stomatology, Tongji Medical Collage, Huazhong University of Science and Technology, and the Key Laboratory of Oral and Maxillofacial Development and Regeneration of Hubei ProvinceDepartment of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and TechnologyThe Cyrus Tang Hematology Center, Soochow UniversityDepartment of Medicine, Hematology, University Hospitals Cleveland Medical Center and Case Western Reserve UniversitySchool of Biomedical Engineering, Faculty of Engineering, The University of SydneyThe Centenary Institute, University of SydneyDepartment 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 TechnologyAbstract 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.https://doi.org/10.1038/s41467-024-47493-0 |
| spellingShingle | 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 Chao Fang Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis Nature Communications |
| title | Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis |
| title_full | Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis |
| title_fullStr | Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis |
| title_full_unstemmed | Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis |
| title_short | Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis |
| title_sort | protein disulfide isomerase cleaves allosteric disulfides in histidine rich glycoprotein to regulate thrombosis |
| url | https://doi.org/10.1038/s41467-024-47493-0 |
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