Mutations of the Serine Protease CAP1/Prss8 Lead to Reduced Embryonic Viability, Skin Defects, and Decreased ENaC Activity

Frateschi, Simona; Keppner, Anna; Malsure, Sumedha; Iwaszkiewicz, Justyna; Sergi, Chloé; Mérillat, Anne-Marie; Fowler-Jaeger, Nicole; Randrianarison, Nadia; Planès, Carole; Hummler, Edith

doi:10.1016/j.ajpath.2012.05.007

Cited by 36 publications

(62 citation statements)

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“…2 Of high clinical relevance, both transient and late treatment with ICG-001 restored podocyte function and repressed proteinuria, renal inflammation, and fibrosis. The latter is consistent with the findings of many studies that documented potent antifibrotic effects of canonical Wnt signaling blockade in the kidney, 4 lung, 5 skin, 6 and other organs. It also provides an exciting link between the RAS, TGF-b, and the Wnt/b-catenin pathway.…”

Section: Disclosuressupporting

confidence: 79%

“…7 Recent data also demonstrate that TGF-b stimulates canonical Wnt signaling by decreasing the expression of the Wnt antagonist Dickkopf-1, highlighting how both pathways interact to mediate fibrotic diseases. 6 Together with TGF-b1, b-catenin also contributes to the epithelial cell phenotype switch known as…”

Section: Disclosuresmentioning

confidence: 99%

“…While there is some evidence that kallikrein and prostasin may have a role in activating ENaC in the distal nephron or in other epithelia, 5,6 the key proteases responsible for cleaving the g subunit at a site distal to the inhibitory track under specific pathophysiologic conditions have not been clearly defined. To complicate matters, proteases function in cascades (e.g., clotting factors).…”

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confidence: 99%

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Ray¹,

Kleyman

2015

Journal of the American Society of Nephrology

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Studies over the past decade have shed light on how proteases activate the epithelial sodium channel (ENaC). Two ENaC subunits (a and g) have short stretches of embedded amino acid residues that inhibit the channel. Following proteasedependent cleavage of these subunits at sites flanking these inhibitory tracks, fragments are released and channels are activated.The serine protease furin is expressed in the trans-Golgi network and processes proteins transiting through the biosynthetic pathway. Furin cleaves the a subunit of ENaC twice at sites flanking an inhibitory track, transitioning channels from a low-to a moderate-activity state. Furin cleaves the g subunit once, preceding its inhibitory track. Subsequent cleavage by a second protease at a site distal to the g subunit inhibitory track releases another inhibitory track and transitions ENaC to a high activity state. 1,2 A population of channels that have bypassed proteolytic processing has been observed at the cell surface, adding a layer of complexity regarding channel regulation by proteases (for reviews, see Kashlan and Kleyman 3 and Kleyman et al. 4 ).A growing number of proteases have been shown to cleave the g subunit at sites distal to the inhibitory track, including prostasin, transmembrane protease serine 4 (TMPRSS4), matriptase, kallikrein, plasmin, and elastase. While there is some evidence that kallikrein and prostasin may have a role in activating ENaC in the distal nephron or in other epithelia, 5,6 the key proteases responsible for cleaving the g subunit at a site distal to the inhibitory track under specific pathophysiologic conditions have not been clearly defined. To complicate matters, proteases function in cascades (e.g., clotting factors). Differentiating upstream proteases from those that directly cleave and activate the channel under different states is challenging. In addition, it is likely that we have not identified all of the proteases that can cleave and activate ENaC.Multiple lines of evidence suggest that ENaC processing and activation is a physiologically relevant phenomenon. In the context of extracellular volume depletion or aldosterone administration in the absence volume depletion, increases in channel expression at the cell surface and proteolytic processing of the a and g subunits have been described. 7,8 Prostasin and/or kallikrein could have a role in cleaving the g subunit in these settings. In the setting of proteinuria, filtration of plasminogen by damaged glomeruli and its subsequent conversion to plasmin by tubular urokinase may activate ENaC, contributing to the renal sodium retention seen in this setting. 9,10 Antibodies directed against the amino-or carboxyl-termini of ENaC subunits can readily differentiate cleaved from noncleaved ENaC subunits. 11 The challenge is demonstrating that a subunit has been cleaved twice, shedding an inhibitory track. 10,12 In this issue of JASN, Zachar et al. address important questions regarding the proteolytic processing of the g subunit in human kidney. 13 Specifically, they exa...

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Section: Disclosuressupporting

confidence: 79%

Section: Disclosuresmentioning

confidence: 99%

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Cutting It Out

Ray¹,

Kleyman

2015

Journal of the American Society of Nephrology

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“…Previous studies have emphasized the importance of CAP1/Prss8 in vivo [32][33][34][35] and its implication in ENaC regulation in alveolar fluid clearance and lung fluid balance. 26 In colon, we clearly identify CAP1/Prss8 as a protease activating ENaC in vivo, because on RS and LS diets, ENaC-mediated transport becomes limiting in Prss8 KO mice (Figure 7).…”

Section: Cap1 Regulates Colon Enac Activity By Blunting Its Circadianmentioning

confidence: 99%

Colon-Specific Deletion of Epithelial Sodium Channel Causes Sodium Loss and Aldosterone Resistance

Malsure

Wang

Charles

et al. 2014

Journal of the American Society of Nephrology

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Aldosterone promotes electrogenic sodium reabsorption through the amiloride-sensitive epithelial sodium channel (ENaC). Here, we investigated the importance of ENaC and its positive regulator channel-activating protease 1 (CAP1/Prss8) in colon. Mice lacking the aENaC subunit in colonic superficial cells (Scnn1a KO ) were viable, without fetal or perinatal lethality. Control mice fed a regular or low-salt diet had a significantly higher amiloride-sensitive rectal potential difference (ΔPD amil ) than control mice fed a high-salt diet. In Scnn1a KO mice, however, this salt restriction-induced increase in ΔPD amil did not occur, and the circadian rhythm of ΔPD amil was blunted. Plasma and urinary sodium and potassium did not change with regular or high-salt diets or potassium loading in control or Scnn1a KO mice. However, Scnn1a KO mice fed a low-salt diet lost significant amounts of sodium in their feces and exhibited high plasma aldosterone and increased urinary sodium retention. Mice lacking the CAP1/Prss8 in colonic superficial cells (Prss8 KO ) were viable, without fetal or perinatal lethality. Compared with controls, Prss8 KO mice fed regular or low-salt diets exhibited significantly reduced ΔPD amil in the afternoon, but the circadian rhythm was maintained. Prss8 KO mice fed a low-salt diet also exhibited sodium loss through feces and higher plasma aldosterone levels. Thus, we identified CAP1/Prss8 as an in vivo regulator of ENaC in colon. We conclude that, under salt restriction, activation of the renin-angiotensin-aldosterone system in the kidney compensated for the absence of ENaC in colonic surface epithelium, leading to colon-specific pseudohypoaldosteronism type 1 with mineralocorticoid resistance without evidence of impaired potassium balance.

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“…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. Subsequent studies using tissue-specific knockout mice to bypass the postnatal lethality revealed that matriptase and/or prostasin play crucial roles in epithelial development and function in a wide variety of mouse tissues including placenta, skin, salivary gland, intestines, lungs and thymus (Frateschi et al, 2012;List et al, 2009;Malsure et al, 2014;Planes et al, 2010;Szabo et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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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Mutations of the Serine Protease CAP1/Prss8 Lead to Reduced Embryonic Viability, Skin Defects, and Decreased ENaC Activity

Cited by 36 publications

References 47 publications

Cutting It Out

Cutting It Out

Colon-Specific Deletion of Epithelial Sodium Channel Causes Sodium Loss and Aldosterone Resistance

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

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