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).

中文翻译：

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深入了解麦芽糖酶-前列腺素蛋白水解系统的调控

属于丝氨酸蛋白酶S1A亚家族的膜相关前列腺素和matriptase对于上皮的发育和维持至关重要。这两种蛋白酶彼此相关，并且都受蛋白酶抑制剂HAI-1和HAI-2调控。丝氨酸蛋白酶的S1A亚家族通常作为需要切割事件以获得活性的无活性酶原产生。但是，与常见情况相反，Matriptase的酶原形式表现出蛋白水解活性，对于活化的对应物，它可以被HAI-1和HAI-2抑制。我们提供有力的证据，证明前列腺素也以其酶原形式表现出蛋白水解活性。此外，我们表明酶原前列腺素的活性可以被HAI-1和HAI-2抑制。我们报告酶原前列腺素能够激活酶原matriptase，但不能激活其自身的酶原形式。我们提出了一种不寻常的酶与酶的关系，该酶与酶的关系由苹果酸蛋白酶和前列腺素的蛋白水解活性酶原形式组成，并受HAI-1和HAI-2的控制，位于上皮中重要蛋白水解途径的顶峰。这种蛋白水解系统中的平衡紊乱很可能会通过酶原双歧杆菌酶和酶原前列腺素的双重作用而导致快速有效地激活麦芽三磷酸酶。先前的研究表明，Matriptase的酶原形式可以执行蛋白酶的正常蛋白水解功能，而过量的Matriptase激活则可能导致癌变。