Insights into the regulation of the matriptase-prostasin proteolytic system
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Insights into the regulation of the matriptase-prostasin proteolytic system. / Holt-Danborg, Lasse; Skovbjerg, Signe; Goderum, Kristian W.; Nonboe, Annika W.; Stankevic, Evelina; Frost, Ásdis K.; Vitved, Lars; Jensen, Jan K.; Vogel, Lotte K.
I: The Biochemical journal, Bind 477, Nr. 22, 2020, s. 4349-4365.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Insights into the regulation of the matriptase-prostasin proteolytic system
AU - Holt-Danborg, Lasse
AU - Skovbjerg, Signe
AU - Goderum, Kristian W.
AU - Nonboe, Annika W.
AU - Stankevic, Evelina
AU - Frost, Ásdis K.
AU - Vitved, Lars
AU - Jensen, Jan K.
AU - Vogel, Lotte K.
PY - 2020
Y1 - 2020
N2 - 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).
AB - 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).
KW - HAI-1
KW - HAI-2
KW - matriptase
KW - prostasin
KW - serine proteases
KW - zymogen activity
U2 - 10.1042/BCJ20200630
DO - 10.1042/BCJ20200630
M3 - Journal article
C2 - 33094801
AN - SCOPUS:85096946981
VL - 477
SP - 4349
EP - 4365
JO - Biochemical Journal
JF - Biochemical Journal
SN - 0264-6021
IS - 22
ER -
ID: 252676745