The membrane-associated prostasin and matriptase belonging to the S1A subfamily of serine proteases, are critical for epithelial development and maintenance. The two proteases are involved in the activation of each other and are both regulated by the protease inhibitors, HAI-1 and HAI-2. The S1A subfamily of serine proteases are generally produced as inactive zymogens requiring a cleavage event to obtain activity. However, contrary to the common case, the zymogen form of matriptase exhibits proteolytic activity, which can be inhibited by HAI-1 and HAI-2, as for the activated counterpart. We provide strong evidence that also prostasin exhibits proteolytic activity in its zymogen form. Furthermore, we show that the activity of zymogen prostasin can be inhibited by HAI-1 and HAI-2. We report that zymogen prostasin is capable of activating zymogen matriptase, but unable to activate its own zymogen form. We propose the existence of an unusual enzyme–enzyme relationship consisting of proteolytically active zymogen forms of both matriptase and prostasin, kept under control by HAI-1 and HAI-2, and located at the pinnacle of an important proteolytic pathway in epithelia. Perturbed balance in this proteolytic system is likely to cause rapid and efficient activation of matriptase by the dual action of zymogen matriptase and zymogen prostasin. Previous studies suggest that the zymogen form of matriptase performs the normal proteolytic functions of the protease, whereas excess matriptase activation likely causes carcinogenesis. HAI-1 and HAI-2 are thus important for the prevention of matriptase activation whether catalysed by zymogen/activated prostasin (this study) or zymogen/activated matriptase (previous studies).
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November 2020
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In this issue Kalogeropulou and colleagues (pp. 4397–4423) demonstrate that endogenous Rab29 does not impact basal or stimulated LRRK2 pathway activity. The cover image shows stained transgenic Rab29-overexpressing mouse cells. Image provided by Dario Alessi.
Research Article|
November 26 2020
Insights into the regulation of the matriptase-prostasin proteolytic system
Lasse Holt-Danborg;
Lasse Holt-Danborg
*
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Writing - review & editing
1Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Signe Skovbjerg;
Signe Skovbjerg
*
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Visualization, Writing - review & editing
1Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Kristian W. Goderum;
Kristian W. Goderum
Data curation, Formal analysis, Investigation
1Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Annika W. Nonboe;
Annika W. Nonboe
Conceptualization, Formal analysis, Visualization, Writing - original draft
1Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Evelina Stankevic;
Evelina Stankevic
Data curation, Investigation
1Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Ásdis K. Frost;
Ásdis K. Frost
2Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
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Lars Vitved;
Lars Vitved
Resources
3Department of Cancer and Inflammation, University of Southern Denmark, Odense, Denmark
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Jan K. Jensen;
Jan K. Jensen
Resources, Formal analysis, Supervision, Funding acquisition, Writing - review & editing
2Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
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Lotte K. Vogel
1Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
Correspondence: Lotte K. Vogel (vogel@sund.ku.dk)
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Publisher: Portland Press Ltd
Received:
August 20 2020
Revision Received:
October 16 2020
Accepted:
October 22 2020
Accepted Manuscript online:
October 23 2020
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2020
Biochem J (2020) 477 (22): 4349–4365.
Article history
Received:
August 20 2020
Revision Received:
October 16 2020
Accepted:
October 22 2020
Accepted Manuscript online:
October 23 2020
Citation
Lasse Holt-Danborg, Signe Skovbjerg, Kristian W. Goderum, Annika W. Nonboe, Evelina Stankevic, Ásdis K. Frost, Lars Vitved, Jan K. Jensen, Lotte K. Vogel; Insights into the regulation of the matriptase-prostasin proteolytic system. Biochem J 27 November 2020; 477 (22): 4349–4365. doi: https://doi.org/10.1042/BCJ20200630
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