Delineation of proteolytic and non-proteolytic functions of membrane-anchored serine protease Prss8/prostasin

The membrane-anchored serine proteases prostasin and matriptase initiate a cell surface proteolytic pathway essential for epithelial function. Mice expressing only catalytically-inactive prostasin, unlike prostasin null mice, are viable, indicating that at least some of prostasin's functions are non-proteolytic. Here we used knockin mice expressing catalytically-inactive prostasin (Prss8^Ki/Ki) to show that prostasin's physiological and pathological functions vary as to their dependence on its catalytic activity. While prostasin null (Prss8^−/−) mice exhibited partial embryonic and complete perinatal lethality, Prss8^Ki/Ki mice displayed normal pre- and postnatal survival. Unexpectedly, catalytically-inactive prostasin caused embryonic lethality in mice lacking its cognate inhibitors, HAI-1 or HAI-2. Proteolytically-inactive prostasin, unlike the wildtype protease, was unable to activate matriptase during placentation. Surprisingly, all essential functions of prostasin in embryonic and postnatal development were compensated for by loss of HAI-1, indicating that prostasin is only required for mouse development and overall viability in the presence of this inhibitor. This study expands our knowledge of non-proteolytic functions of membrane-anchored serine proteases and provides unexpected new data as to the mechanistic interactions between matriptase and prostasin in the context of epithelial development.