title: Delineation of proteolytic and non-proteolytic functions of the membrane-anchored serine protease prostasin.
abstract: The membrane-anchored serine proteases prostasin (PRSS8) and matriptase (ST14) initiate a cell surface proteolytic pathway essential for epithelial function. Mice expressing only catalytically inactive prostasin are viable, unlike prostasin null mice, indicating that at least some prostasin functions are non-proteolytic. Here we used knock-in mice expressing catalytically inactive prostasin (Prss8(Ki/Ki)) to show that the physiological and pathological functions of prostasin vary in their dependence on its catalytic activity. Whereas prostasin null mice exhibited partial embryonic and complete perinatal lethality, Prss8(Ki/Ki) mice displayed normal prenatal and postnatal survival. Unexpectedly, catalytically inactive prostasin caused embryonic lethality in mice lacking its cognate inhibitors HAI-1 (SPINT1) or HAI-2 (SPINT2). Proteolytically inactive prostasin, unlike the wild-type 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 on the mechanistic interactions between matriptase and prostasin in the context of epithelial development.
authors.affiliation: Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Roman
authors.identifier: 0000-0002-7661-8718
authors.initials: R
authors.lastname: Szabo
authors.affiliation: Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Taliya
authors.initials: T
authors.lastname: Lantsman
authors.affiliation: Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02110, USA.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Peters
authors.affiliation: Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA thomas.bugge@nih.gov.
authors.forename: Thomas H
authors.identifier: 0000-0001-7046-4060
authors.initials: TH
authors.lastname: Bugge
mesh_terms: D000818:Animals; D005260:Female; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010929:Placentation; D011247:Pregnancy; D053491:Proteinase Inhibitory Proteins, Secretory; D059748:Proteolysis; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism*; D000099271:Prostasin
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D012697:Serine Endopeptidases; D057057:Serine Proteases; D000099271:Prostasin; C504591:Spint1 protein, mouse; C533525:Spint2 protein, mouse; C485595:matriptase
keywords: Cell surface proteolysis; Epithelial development; Placental labyrinth; Serine protease