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

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收录情况： ◇ 自然指数

作者：
Lv Keyu[1] * ; Chen Shuai[1,2] * ; Xu Xulin[1,3,4] * ; Chiu Joyce[5] ; Wang Haoqing J[6,7] ; Han Yunyun[8] ; Yang Xiaodan[8] ; Bowley Sheryl R[9] ; Wang Hao[1] ; Tang Zhaoming[10] ; Tang Ning[11] ; Yang Aizhen[12] ; Yang Shuofei[13] ; Wang Jinyu[14] ; Jin Si[15] ; Wu Yi[12] ; Schmaier Alvin H[16] ; Ju Lining A[6,7] ; Hogg Philip J[5] ; Fang Chao[1,3,4] ;
单位： [1]Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic InfectiousDiseases,HuazhongUniversity of Science and Technology,Wuhan 430030Hubei,China. [2]Department of Pharmacology, School of BasicMedicine, Guizhou University of TraditionalChinese Medicine,Guiyang 550025Guizhou,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, HarvardMedical 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, TongjiMedical 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 ofMedicine, Shanghai Jiao Tong University, Shanghai 200127, China. [14]School of Stomatology, Tongji Medical Collage, Huazhong University of Science and Technology, and the Key Laboratory ofOral and MaxillofacialDevelopment and Regeneration ofHubei Province, Wuhan 430030Hubei,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 CaseWestern Reserve University, Cleveland, OH 44106, USA.
出处：
DOI： 10.1038/s41467-024-47493-0

摘要：
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.© 2024. The Author(s).

基金：
This work was supported in part by the National Natural Science Foundation of China (92169114 and 81802932) (C.F.), the Natural Science Fund for Distinguished Young Scholars ofHubei Province (2022CFA054) (C.F.), the National Key R&D Program of China (2018YFE0113600) (C.F.), the Global Research Award and the Supplement Award from the American Society of Hematology (C.F.), a HUST-QMUL joint research grant (2022-HUST-QMUL-SPRF-01) (C.F.), a HUST-USYD-JRC grant (C.F.), the Open Project of Hubei Key Laboratory of Wudang Local Chinese Medicine Research from the Hubei University of Medicine (WDCM2023001/2022001) (X.X.), a National Health and Medical Research Council (NHMRC) of Australia Ideas Grant (APP2003904) (L.A.J.), an NSW Cardiovascular Capacity Building Program Early-Mid Career Researcher Grant (L.A.J.), MRFF Cardiovascular Health Mission Grants (MRF2016165 and MRF2023977) (L.A.J.), and a National Heart Foundation VanguardGrant (106979) (L.A.J.). L.A.J. is an Australian Heart Foundation Future Leader Fellow Level 2 (105863) and a Snow Medical Research Foundation Fellow (2022SF176).
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外文
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出版当年[2023]版：
大类 | 1 区 综合性期刊
小类 | 1 区 综合性期刊
最新[2025]版：
大类 | 1 区 综合性期刊
小类 | 1 区 综合性期刊
第一作者：
第一作者单位： [1]Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic InfectiousDiseases,HuazhongUniversity of Science and Technology,Wuhan 430030Hubei,China.
共同第一作者：
通讯作者：
通讯机构： [1]Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic InfectiousDiseases,HuazhongUniversity of Science and Technology,Wuhan 430030Hubei,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.
推荐引用方式(GB/T 7714)：
Lv Keyu,Chen Shuai,Xu Xulin,et al.Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis[J].Nature Communications.2024,15(1):3129.doi:10.1038/s41467-024-47493-0.
APA：
Lv Keyu,Chen Shuai,Xu Xulin,Chiu Joyce,Wang Haoqing J...&Fang Chao.(2024).Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis.Nature Communications,15,(1)
MLA：
Lv Keyu,et al."Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis".Nature Communications 15..1(2024):3129

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