Cleavage-Dependent and Independent Role of the Serine Protease CAP1/Prss8

Abstract

Serine protease are enzymes involved in the regulation of many biological processes, and generally exert their function by cleaving peptide bonds through the catalytic triad of histidine, aspartate and serine. The channel-activating protease 1 (CAP1/protease serine S1 family member 8 (Prss8) is a membrane-anchored serine protease expressed in the epithelium of several organs, such as the skin, colon, lung and kidney, and can be released in the extracellular space by the action of phospholipase C. CAP1/Prss8 was one of the the first of several membrane-bound serine proteases, such as CAP2/Tmptrss4 and CAP3/matriptase, found to activate the epithelial sodium channel (ENaC) in-vitro. Since these studies strongly suggested a non-enzymatic function of CAP1/Prss8, we over-expressed the catalytically inactive form of CAP1/Prss8 and asked whether we can negate the obtained phenotype by crossing these mice with mice lacking the protease-activated receptor 2, that we previously identified as downstream target substrate. Since serine protease activity needs to be tighly regulated, we also asked the question whether the putative serine protease inhibitor nexin-1 is able to block CAP1/Prss8 in vitro and in vivo.Our results demonstrate the ability of a catalytically inactive serine protease to induce disease when ectopically expressed, and a novel inhibitory interaction that does not depend on its catalytic site.