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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) 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, Prss8Ki/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.

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Contributors RA, TSA, JPS, SJH conceptualised the idea. AM, AP, AA, NP, MD, TM, TL, NF were involved in data collection. RA was involved in data analytics. LN was involved in analytical planning and statistical guidance. JPS and SJH supervised the study. All authors were involved in drafting the manuscript, intellectual design and critical revision of the manuscript for intellectual content.

Objective The aim of this study was to determine if cervical dysplasia during pregnancy is associated with pregnancy complications, including preterm delivery and pre-eclampsia. Study Design A retrospective cohort analyses was performed with propensity-score matching to compare complication rates between pregnant women without history of abnormal cervical cancer screening and pregnant women referred for cervical dysplasia assessment to colposcopy clinic. A composite outcome of pregnancy complications included intra-amniotic infection, preterm premature rupture of membranes, pre-eclampsia, preterm delivery, low birth weight, oligohydramnios, and intrauterine fetal demise. Complication rates were compared between women with and without cervical dysplasia using logistic regression models. Results Overall cohort included 2,814 women, 279 of whom attended colposcopy clinic for cervical dysplasia assessment. Propensity score–matched cohort included 1,459 women, 274 of whom attended colposcopy clinic. Composite complications of pregnancy rates were not significantly different between control and colposcopy groups in both cohorts (25.3% and 29.0%, P = 0.20; 26.5% and 29.3%, P = 0.45). Dysplasia was not associated with composite pregnancy complications in overall and matched cohorts (odds ratio [OR] = 1.09, 95% confidence interval [CI]: 0.77–1.56) and (OR = 1.03, 95% CI: 0.72–1.49). When cervical dysplasia was determined on biopsy or colposcopy, dysplasia was not associated with complications in the overall and matched cohorts. Conclusion Biopsy and/or colposcopy determined cervical dysplasia during pregnancy was not associated with pregnancy complications.

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