Abstract
The membrane-associated serine proteases matriptase and prostasin are believed to function in close partnership. Their zymogen activation has been reported to be tightly coupled, either as a matriptase-initiated proteolytic cascade or through a mutually dependent mechanism involving the formation of a reciprocal zymogen activation complex. Here we show that this putative relationship may not apply in the context of human matriptase and prostasin. First, the tightly coupled proteolytic cascade between matriptase and prostasin might not occur when modest matriptase activation is induced by sphingosine 1-phospahte in human mammary epithelial cells. Second, prostasin is not required and/or involved in matriptase autoactivation because matriptase can undergo zymogen activation in cells that do not endogenously express prostasin. Third, matriptase is not required for and/or involved in prostasin activation, since activated prostasin can be detected in cells expressing no endogenous matriptase. Finally, matriptase and prostasin both undergo zymogen activation through an apparently un-coupled mechanism in cells endogenously expressing both proteases, such as in Caco-2 cells. In these human enterocytes, matriptase is detected primarily in the zymogen form and prostasin predominantly as the activated form, either in complexes with protease inhibitors or as the free active form. The negligible levels of prostasin zymogen with high levels of matriptase zymogen suggests that the reciprocal zymogen activation complex is likely not the mechanism for matriptase zymogen activation. Furthermore, high level prostasin activation still occurs in Caco-2 variants with reduced or absent matriptase expression, indicating that matriptase is not required and/or involved in prostasin zymogen activation. Collectively, these data suggest that any functional relationship between natural endogenous human matriptase and prostasin does not occur at the level of zymogen activation.
Highlights
The type 2 transmembrane serine protease matriptase and the glycosylphosphatidylinositol (GPI)-anchored serine protease prostasin contribute to the formation of the epidermal barrier in mouse skin apparently by working together in a tightly coupled proteolytic cascade
Support for this conclusion comes from several lines of evidence: 1) Targeted deletion of matriptase or prostasin results in almost identical epidermal defects in the skin of the respective knockout mice [1,2]. 2) Matriptase and prostasin are co-expressed in the uppermost layer of viable keratinocytes in the mouse epidermis and so could act in concert to contribute to the later stages of epidermal differentiation and the formation of the epidermal barrier [3]. 3) Prostasin zymogen activation does not appear to occur in the skin of matriptase knockout mice [3]
Induction of simultaneous matriptase and prostasin zymogen activation, followed by rapid HAI-1-mediated inhibition of the nascent active matriptase and prostasin, has been observed in HaCaT human keratinocytes when the cells were transiently exposed to a pH 6.0 buffer [9]
Summary
The type 2 transmembrane serine protease matriptase and the glycosylphosphatidylinositol (GPI)-anchored serine protease prostasin contribute to the formation of the epidermal barrier in mouse skin apparently by working together in a tightly coupled proteolytic cascade Support for this conclusion comes from several lines of evidence: 1) Targeted deletion of matriptase or prostasin results in almost identical epidermal defects in the skin of the respective knockout mice [1,2]. 3) Prostasin zymogen activation does not appear to occur in the skin of matriptase knockout mice [3] These data, along with the observation that activation of human matriptase zymogen occurs by autoactivation [4], support the conclusion that matriptase and prostasin function as a proteolytic cascade with matriptase as an upstream activator and prostasin as a downstream substrate contributing to epidermal barrier formation. The active prostasin produced could act as the sole downstream effector of matriptase, participating directly in the formation of the epidermal barrier of mouse skin
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