title: Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation.
abstract: Loss of either hepatocyte growth factor activator inhibitor (HAI)-1 or -2 is associated with embryonic lethality in mice, which can be rescued by the simultaneous inactivation of the membrane-anchored serine protease, matriptase, thereby demonstrating that a matriptase-dependent proteolytic pathway is a critical developmental target for both protease inhibitors. Here, we performed a genetic epistasis analysis to identify additional components of this pathway by generating mice with combined deficiency in either HAI-1 or HAI-2, along with genes encoding developmentally co-expressed candidate matriptase targets, and screening for the rescue of embryonic development. Hypomorphic mutations in Prss8, encoding the GPI-anchored serine protease, prostasin (CAP1, PRSS8), restored placentation and normal development of HAI-1-deficient embryos and prevented early embryonic lethality, mid-gestation lethality due to placental labyrinth failure, and neural tube defects in HAI-2-deficient embryos. Inactivation of genes encoding c-Met, protease-activated receptor-2 (PAR-2), or the epithelial sodium channel (ENaC) alpha subunit all failed to rescue embryonic lethality, suggesting that deregulated matriptase-prostasin activity causes developmental failure independent of aberrant c-Met and PAR-2 signaling or impaired epithelial sodium transport. Furthermore, phenotypic analysis of PAR-1 and matriptase double-deficient embryos suggests that the protease may not be critical for focal proteolytic activation of PAR-2 during neural tube closure. Paradoxically, although matriptase auto-activates and is a well-established upstream epidermal activator of prostasin, biochemical analysis of matriptase- and prostasin-deficient placental tissues revealed a requirement of prostasin for conversion of the matriptase zymogen to active matriptase, whereas prostasin zymogen activation was matriptase-independent.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Roman
authors.initials: R
authors.lastname: Szabo
authors.forename: Katiuchia
authors.initials: K
authors.lastname: Uzzun Sales
authors.forename: Peter
authors.initials: P
authors.lastname: Kosa
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Shylo
authors.forename: Sine
authors.initials: S
authors.lastname: Godiksen
authors.forename: Karina K
authors.initials: KK
authors.lastname: Hansen
authors.forename: Stine
authors.initials: S
authors.lastname: Friis
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Lotte K
authors.initials: LK
authors.lastname: Vogel
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
authors.forename: Eric
authors.initials: E
authors.lastname: Camerer
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
mesh_terms: D000818:Animals; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D004843:Epistasis, Genetic; D005260:Female; D005804:Genes, Lethal; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D054259:Neural Tube / Q000196:embryology / Q000378:metabolism; D010929:Placentation / Q000235:genetics; D011247:Pregnancy; D053491:Proteinase Inhibitory Proteins, Secretory; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000099271:Prostasin
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D044462:Receptors, Proteinase-Activated; D012697:Serine Endopeptidases; D000099271:Prostasin; C504591:Spint1 protein, mouse; C533525:Spint2 protein, mouse; C485595:matriptase