The membrane-anchored serine protease prostasin (CAP1/PRSS8) supports epidermal development and postnatal homeostasis independent of its enzymatic activity.
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 enzymatic 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 (Prss8(Cat-/Cat-) mice), develop barrier function and are healthy when followed for up to 20 weeks. This striking difference could not be explained by genetic modifiers or by maternal effects, as these divergent phenotypes were displayed by Prss8(-/-) and Prss8(Cat-/Cat-) mice born within the same litter. Furthermore, Prss8(Cat-/Cat-) mice were able to regenerate epidermal covering following cutaneous wounding. This 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.
From the Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, the Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111.
Diane E
DE
Peters
From the Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892.
Roman
R
Szabo
From the Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, the Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
Stine
S
Friis
From the Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892.
Natalia A
NA
Shylo
From the Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, the Clinical Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892.
Katiuchia
K
Uzzun Sales
the Connective Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, and.
Kenn
K
Holmbeck
From the Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, thomas.bugge@nih.gov.
Thomas H
TH
Bugge
D000818:Animals; D000831:Animals, Newborn; D055162:Biocatalysis; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics; D002462:Cell Membrane / Q000201:enzymology*; D004817:Epidermis / Q000201:enzymology* / Q000254:growth & development / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D006720:Homozygote; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017354:Point Mutation; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000099271:Prostasin
D012697:Serine Endopeptidases; D000099271:Prostasin
Allosteric Regulation; Enzyme Catalysis; Enzyme Mechanisms; Epidermal Development; Epithelium; Pericellular Proteolysis; Serine Protease