The Membrane-Anchored Serine Protease Prostasin (CAP1/PRSS8) Supports Epidermal Development and Postnatal Homeostasis Independent of its Enzymatic Activity [Developmental Biology]
April 4th, 2014 by Peters, D. E., Szabo, R., Friis, S., Shylo, N. A., Sales, K. U., Holmbeck, K., Bugge, T. H.
The membrane-anchored serine protease prostasin (CAP1/PRSS8) is part of a cell surface proteolytic cascade that is essential for epithelial barrier formation and homeostasis. Here we report the surprising finding that prostasin executes these functions independent of its own catalytic activity. Prostasin null (Prss8-/-) mice lack barrier formation and display fatal postnatal dehydration. In sharp contrast, mice homozygous for a point mutation in the Prss8 gene, which causes the substitution of the active site serine within the catalytic histidine-aspartate-serine triad with alanine and renders prostasin catalytically-inactive (Prss8Cat-/Cat- mice), develop barrier function and are viable and healthy when followed for up to twenty weeks. This striking difference could not be explained by genetic modifiers or by maternal effects, as these divergent phenotypes were displayed by Prss8-/- and Prss8Cat-/Cat- mice born within the same litter. Furthermore, Prss8Cat-/Cat- mice were able to regenerate epidermal covering following cutaneous wounding.The study provides the first demonstration that essential in vivo functions of prostasin are executed by a non-enzymatic activity of this unique membrane-anchored serine protease.