Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation.
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...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002937&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850190329543655424 |
|---|---|
| author | Roman Szabo Katiuchia Uzzun Sales Peter Kosa Natalia A Shylo Sine Godiksen Karina K Hansen Stine Friis J Silvio Gutkind Lotte K Vogel Edith Hummler Eric Camerer Thomas H Bugge |
| author_facet | Roman Szabo Katiuchia Uzzun Sales Peter Kosa Natalia A Shylo Sine Godiksen Karina K Hansen Stine Friis J Silvio Gutkind Lotte K Vogel Edith Hummler Eric Camerer Thomas H Bugge |
| author_sort | Roman Szabo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9de82db345fb45cea6db9244198f55ad |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-9de82db345fb45cea6db9244198f55ad2025-08-20T02:15:19ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-01-0188e100293710.1371/journal.pgen.1002937Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation.Roman SzaboKatiuchia Uzzun SalesPeter KosaNatalia A ShyloSine GodiksenKarina K HansenStine FriisJ Silvio GutkindLotte K VogelEdith HummlerEric CamererThomas H BuggeLoss 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002937&type=printable |
| spellingShingle | Roman Szabo Katiuchia Uzzun Sales Peter Kosa Natalia A Shylo Sine Godiksen Karina K Hansen Stine Friis J Silvio Gutkind Lotte K Vogel Edith Hummler Eric Camerer Thomas H Bugge Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation. PLoS Genetics |
| title | Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation. |
| title_full | Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation. |
| title_fullStr | Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation. |
| title_full_unstemmed | Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation. |
| title_short | Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation. |
| title_sort | reduced prostasin cap1 prss8 activity eliminates hai 1 and hai 2 deficiency associated developmental defects by preventing matriptase activation |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002937&type=printable |
| work_keys_str_mv | AT romanszabo reducedprostasincap1prss8activityeliminateshai1andhai2deficiencyassociateddevelopmentaldefectsbypreventingmatriptaseactivation AT katiuchiauzzunsales reducedprostasincap1prss8activityeliminateshai1andhai2deficiencyassociateddevelopmentaldefectsbypreventingmatriptaseactivation AT peterkosa reducedprostasincap1prss8activityeliminateshai1andhai2deficiencyassociateddevelopmentaldefectsbypreventingmatriptaseactivation AT nataliaashylo reducedprostasincap1prss8activityeliminateshai1andhai2deficiencyassociateddevelopmentaldefectsbypreventingmatriptaseactivation AT sinegodiksen reducedprostasincap1prss8activityeliminateshai1andhai2deficiencyassociateddevelopmentaldefectsbypreventingmatriptaseactivation AT karinakhansen reducedprostasincap1prss8activityeliminateshai1andhai2deficiencyassociateddevelopmentaldefectsbypreventingmatriptaseactivation AT stinefriis reducedprostasincap1prss8activityeliminateshai1andhai2deficiencyassociateddevelopmentaldefectsbypreventingmatriptaseactivation AT jsilviogutkind reducedprostasincap1prss8activityeliminateshai1andhai2deficiencyassociateddevelopmentaldefectsbypreventingmatriptaseactivation AT lottekvogel reducedprostasincap1prss8activityeliminateshai1andhai2deficiencyassociateddevelopmentaldefectsbypreventingmatriptaseactivation AT edithhummler reducedprostasincap1prss8activityeliminateshai1andhai2deficiencyassociateddevelopmentaldefectsbypreventingmatriptaseactivation AT ericcamerer reducedprostasincap1prss8activityeliminateshai1andhai2deficiencyassociateddevelopmentaldefectsbypreventingmatriptaseactivation AT thomashbugge reducedprostasincap1prss8activityeliminateshai1andhai2deficiencyassociateddevelopmentaldefectsbypreventingmatriptaseactivation |