Proteome analysis of mast cell releasates reveals a role for chymase in the regulation of coagulation factor XIIIA levels via proteolytic degradation

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• 作者：Nicholas J. Shubin ; PhD^a ; Veronika A. Glukhova ; PhD^a ; Morgan Clauson ; BSc^a ; Phuong Truong ; BSc^a ; Magnus Abrink ; PhD^b ; Gunnar Pejler ; PhD^c ; ^d ; Nathan J. White ; MD ; MS^e ; Gail H. Deutsch ; MD^f ; Stephen R. Reeves ; MD ; PhD^a ; ^g ; Tomas Vaisar ; PhD^h ; Richard G. James ; PhD^a ; Adrian M. Piliponsky ; PhD^a ; ^g ; ^{adrian.piliponsky@seattlechildrens.org}
• 关键词：Mast cells ; proteases ; chymase ; proteomics
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：139
• 期：1
• 页码：323-334
• 全文大小：1034 K
• 卷排序：139

文摘

Mast cells are significantly involved in IgE-mediated allergic reactions; however, their roles in health and disease are incompletely understood.ObjectiveWe aimed to define the proteome contained in mast cell releasates on activation to better understand the factors secreted by mast cells that are relevant to the contribution of mast cells in diseases.MethodsBone marrow–derived cultured mast cells (BMCMCs) and peritoneal cell–derived mast cells were used as “surrogates” for mucosal and connective tissue mast cells, respectively, and their releasate proteomes were analyzed by mass spectrometry.ResultsOur studies showed that BMCMCs and peritoneal cell–derived mast cells produced substantially different releasates following IgE-mediated activation. Moreover, we observed that the transglutaminase coagulation factor XIIIA (FXIIIA) was one of the most abundant proteins contained in the BMCMC releasates. Mast cell–deficient mice exhibited increased FXIIIA plasma and activity levels as well as reduced bleeding times, indicating that mast cells are more efficient in their ability to downregulate FXIIIA than in contributing to its amounts and functions in homeostatic conditions. We found that human chymase and mouse mast cell protease-4 (the mouse homologue of human chymase) had the ability to reduce FXIIIA levels and function via proteolytic degradation. Moreover, we found that chymase deficiency led to increased FXIIIA amounts and activity, as well as reduced bleeding times in homeostatic conditions and during sepsis.ConclusionsOur study indicates that the mast cell protease content can shape its releasate proteome. Moreover, we found that chymase plays an important role in the regulation of FXIIIA via proteolytic degradation.