The Membrane-anchored Serine Protease Prostasin (CAP1/PRSS8) Supports Epidermal Development and Postnatal Homeostasis Independent of Its Enzymatic Activity

Peters, Diane E.; Szabo, Roman; Friis, Stine; Shylo, Natalia A.; Sales, Katiuchia Uzzun; Holmbeck, Kenn; Bugge, Thomas H.

doi:10.1074/jbc.m113.541318

Cited by 35 publications

(53 citation statements)

References 24 publications

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“…Although we cannot formally exclude this possibility, the fact that the loss of prostasin function leads to phenotypes that are virtually identical to those observed in the absence of matriptase would suggest that the two proteases regulate developmental functions as part of a single proteolytic system. Genetic background appears to have a considerable effect on the phenotypes associated with the loss of prostasin or matriptase, in particular during embryonic development, as documented by complete embryonic lethality in an inbred C57BL/6J background but partial or complete prenatal survival in several prostasin-or matriptase-deficient strains of mixed background (Hummler et al, 2013;Leyvraz et al, 2005;List et al, 2002;Peters et al, 2014;Szabo et al, 2009aSzabo et al, , 2014R.S. and T.H.B., unpublished).…”

Section: Discussionmentioning

confidence: 99%

“…The essential role of prostasin in mouse postnatal survival is well established (Leyvraz et al, 2005;Peters et al, 2014;Szabo et al, 2012). Reports of its role in embryonic development, however, show far less concordance.…”

Section: Prostasin Is a Crucial Contributor To Mouse Mid-gestational mentioning

confidence: 99%

“…Inactivation of HAI-1, but not HAI-2, results in prostasinindependent postnatal survival Loss of prostasin function leads to a catastrophic loss of the epidermal barrier, the absence of whiskers at birth, and a complete perinatal lethality (Leyvraz et al, 2005;Peters et al, 2014;this study). Unexpectedly, analysis of postnatal survival in the offspring from Spint1 +/− ;Prss8 +/− breeding pairs showed that, whereas all of the HAI-1-expressing Prss8 −/− mice (Spint1 +/+ ;Prss8 −/− or Spint1 +/− ;Prss8 −/− ) died within the first few days after birth, mice ;Prss8 −/− mice at 1 (I) and 4 (J) weeks of age.…”

Section: Prss8mentioning

confidence: 99%

“…Studies using genetically modified mouse strains suggest that the two proteases are part of a single proteolytic cascade that plays a central role in the development and homeostasis of a variety of epithelia. Mice with a systemic loss of either prostasin or matriptase display strain-dependent complete or partial embryonic lethality, and all of the matriptase or prostasin null mice that survive until term die shortly after birth due to fatal dehydration (Hummler et al, 2013;Leyvraz et al, 2005;List et al, 2002;Peters et al, 2014). Detailed phenotypic analysis revealed that the matriptase/prostasin pathway is essential for terminal epidermal differentiation as well as tight junction formation and, as a result, the loss of matriptase or prostasin function leads to a severe defect in epidermal barrier function, and an abnormal hair follicle maturation (Leyvraz et al, 2005;List et al, 2009List et al, , 2003.…”

Section: Introductionmentioning

confidence: 99%

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Delineation of proteolytic and non-proteolytic functions of the membrane-anchored serine protease prostasin

et al. 2016

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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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Section: Discussionmentioning

confidence: 99%

Section: Prostasin Is a Crucial Contributor To Mouse Mid-gestational mentioning

confidence: 99%

Section: Prss8mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Delineation of proteolytic and non-proteolytic functions of the membrane-anchored serine protease prostasin

et al. 2016

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“…Likewise, catalytically inactive prostasin mutants can stimulate the activation of protease-activated receptor-2 in a reconstituted mammalian cell-based system (13). Strong support for a non-proteolytic function of prostasin in vivo has been gained from the observation that mis-expressed catalytically inactive prostasin induces severe skin pathology in transgenic mice (13,14), and in particular, by our recent demonstration that mice expressing only catalytically inactive endogenous prostasin, unlike prostasin null mice, display normal long-term survival (15).…”

mentioning

confidence: 99%

Distinct Developmental Functions of Prostasin (CAP1/PRSS8) Zymogen and Activated Prostasin

Friis

Madsen

Bugge

2016

Journal of Biological Chemistry

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The membrane-anchored serine prostasin (CAP1/PRSS8) is essential for barrier acquisition of the interfollicular epidermis and for normal hair follicle development. Consequently, prostasin null mice die shortly after birth. Prostasin is found in two forms in the epidermis: a one-chain zymogen and a two-chain proteolytically active form, generated by matriptase-dependent activation site cleavage. Here we used gene editing to generate mice expressing only activation site cleavage-resistant (zymogen-locked) endogenous prostasin. Interestingly, these mutant mice displayed normal interfollicular epidermal development and postnatal survival, but had defects in whisker and pelage hair formation. These findings identify two distinct in vivo functions of epidermal prostasin: a function in the interfollicular epidermis, not requiring activation site cleavage, that can be mediated by the zymogen-locked version of prostasin and a proteolysis-dependent function of activated prostasin in hair follicles, dependent on zymogen conversion by matriptase.Prostasin (also known as channel-activating protease-1, CAP1, and PRSS8) is a glycosylphosphatidylinositol-anchored trypsin-like serine protease that is widely expressed in epithelial tissues, including both the interfollicular and the follicular compartments of the epidermis. Loss-of-function genetic studies in mice have uncovered critical functions of prostasin in both the formation of epidermal barrier formation and the formation of whiskers and pelage hair (1, 2). Prostasin is synthesized as an inactive proform (zymogen) that is converted to a catalytically active protease by a single endoproteolytic cleavage in the conserved activation cleavage site (3-6). Prostasin zymogen conversion in the epidermis requires the membraneactivated serine protease matriptase (7-9). This observation, combined with the observation that both matriptase-deficient and prostasin-deficient mice display identical epidermal phenotypes, led to the formulation of the hypothesis that prostasin exerts its functions in this tissue as part of a matriptase-prostasin cell surface zymogen activation cascade (8). Several observations made during the last decade suggest, however, that prostasin may also execute biological functions independent of its own proteolytic activity. For example, in a reconstituted Xenopus oocyte system, prostasin can activate the epithelial sodium channel (ENaC) by inducing proteolytic cleavage of its ␥ subunit to release an inhibitory domain. However, this activation, which can be inhibited by the broad-spectrum serine protease inhibitor, aprotinin, can also be efficiently executed by mutant prostasin variants that lack the catalytic histidine-aspartate-serine triad (10 -12). Likewise, catalytically inactive prostasin mutants can stimulate the activation of protease-activated receptor-2 in a reconstituted mammalian cell-based system (13). Strong support for a non-proteolytic function of prostasin in vivo has been gained from the observation that mis-expressed catalytically inactive pros...

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Matriptase (ST14, Suppressor of Tumorigenicity 14 Protein)

Friis¹

2016

Encyclopedia of Signaling Molecules

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The Membrane-anchored Serine Protease Prostasin (CAP1/PRSS8) Supports Epidermal Development and Postnatal Homeostasis Independent of Its Enzymatic Activity

Cited by 35 publications

References 24 publications

Delineation of proteolytic and non-proteolytic functions of the membrane-anchored serine protease prostasin

Delineation of proteolytic and non-proteolytic functions of the membrane-anchored serine protease prostasin

Distinct Developmental Functions of Prostasin (CAP1/PRSS8) Zymogen and Activated Prostasin

Matriptase (ST14, Suppressor of Tumorigenicity 14 Protein)

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