title: The CAP1/Prss8 catalytic triad is not involved in PAR2 activation and protease nexin-1 (PN-1) inhibition.
abstract: Serine proteases, serine protease inhibitors, and protease-activated receptors (PARs) are responsible for several human skin disorders characterized by impaired epidermal permeability barrier function, desquamation, and inflammation. In this study, we addressed the consequences of a catalytically dead serine protease on epidermal homeostasis, the activation of PAR2 and the inhibition by the serine protease inhibitor nexin-1. The catalytically inactive serine protease CAP1/Prss8, when ectopically expressed in the mouse, retained the ability to induce skin disorders as well as its catalytically active counterpart (75%, n=81). Moreover, this phenotype was completely normalized in a PAR2-null background, indicating that the effects mediated by the catalytically inactive CAP1/Prss8 depend on PAR2 (95%, n=131). Finally, nexin-1 displayed analogous inhibitory capacity on both wild-type and inactive mutant CAP1/Prss8 in vitro and in vivo (64% n=151 vs. 89% n=109, respectively), indicating that the catalytic site of CAP1/Prss8 is dispensable for nexin-1 inhibition. Our results demonstrate a novel inhibitory interaction between CAP1/Prss8 and nexin-1, opening the search for specific CAP1/Prss8 antagonists that are independent of its catalytic activity.
authors.affiliation: Department of Pharmacology and Toxicology and.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Crisante
authors.affiliation: Department of Pharmacology and Toxicology and.
authors.forename: Laura
authors.initials: L
authors.lastname: Battista
authors.affiliation: Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Iwaszkiewicz
authors.affiliation: Department of Pharmacology and Toxicology and.
authors.forename: Valeria
authors.initials: V
authors.lastname: Nesca
authors.affiliation: Department of Pharmacology and Toxicology and.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mérillat
authors.affiliation: Department of Pharmacology and Toxicology and.
authors.forename: Chloé
authors.initials: C
authors.lastname: Sergi
authors.affiliation: Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.affiliation: Department of Pharmacology and Toxicology and simona.frateschi@unil.ch edith.hummler@unil.ch.
authors.forename: Simona
authors.initials: S
authors.lastname: Frateschi
authors.affiliation: Department of Pharmacology and Toxicology and simona.frateschi@unil.ch edith.hummler@unil.ch.
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
mesh_terms: D000818:Animals; D002384:Catalysis; D006706:Homeostasis / Q000502:physiology; D051379:Mice; D010641:Phenotype; D011480:Protease Inhibitors / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D058258:Serpin E2 / Q000378:metabolism*; D012867:Skin / Q000378:metabolism*; D000099271:Prostasin
chemical_list: D011480:Protease Inhibitors; D044464:Receptor, PAR-2; D012697:Serine Endopeptidases; D058258:Serpin E2; D000099271:Prostasin
keywords: enzymatic activity; prostasin; serine protease