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J Physiol
2014 Dec 01;59223:5251-68. doi: 10.1113/jphysiol.2013.267286.
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Cathepsin B contributes to Na+ hyperabsorption in cystic fibrosis airway epithelial cultures.
Tan CD
,
Hobbs C
,
Sameni M
,
Sloane BF
,
Stutts MJ
,
Tarran R
.
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In cystic fibrosis (CF) lung disease, the absence of functional CF transmembrane conductance regulator results in Cl(-)/HCO3 (-) hyposecretion and triggers Na(+) hyperabsorption through the epithelial Na(+) channel (ENaC), which contribute to reduced airway surface liquid (ASL) pH and volume. Prostasin, a membrane-anchored serine protease with trypsin-like substrate specificity has previously been shown to activate ENaC in CF airways. However, prostasin is typically inactive below pH 7.0, suggesting that it may be less relevant in acidic CF airways. Cathepsin B (CTSB) is present in both normal and CF epithelia and is secreted into ASL, but little is known about its function in the airways. We hypothesized that the acidic ASL seen in CF airways may stimulate CTSB to activate ENaC, contributing to Na(+) hyperabsorption and depletion of CF ASL volume. In Xenopus laevis oocytes, CTSB triggered α- and γENaC cleavage and induced an increase in ENaC activity. In bronchial epithelia from both normal and CF donor lungs, CTSB localized to the apical membrane. In normal and CF human bronchial epithelial cultures, CTSB was detected at the apical plasma membrane and in the ASL. CTSB activity was significantly elevated in acidic ASL, which correlated with increased abundance of ENaC in the plasma membrane and a reduction in ASL volume. This acid/CTSB-dependent activation of ENaC was ameliorated with the cell impermeable, CTSB-selective inhibitor CA074, suggesting that CTSB inhibition may have therapeutic relevance. Taken together, our data suggest that CTSB is a pathophysiologically relevant protease that activates ENaC in CF airways.
Adebamiro,
Endogenous protease activation of ENaC: effect of serine protease inhibition on ENaC single channel properties.
2005, Pubmed
Adebamiro,
Endogenous protease activation of ENaC: effect of serine protease inhibition on ENaC single channel properties.
2005,
Pubmed
Alli,
Cathepsin B is secreted apically from Xenopus 2F3 cells and cleaves the epithelial sodium channel (ENaC) to increase its activity.
2012,
Pubmed
,
Xenbase
Barrett,
Cathepsin B, Cathepsin H, and cathepsin L.
1981,
Pubmed
Benos,
Functional domains within the degenerin/epithelial sodium channel (Deg/ENaC) superfamily of ion channels.
1999,
Pubmed
Boucher,
Evidence for airway surface dehydration as the initiating event in CF airway disease.
2007,
Pubmed
Bruns,
Epithelial Na+ channels are fully activated by furin- and prostasin-dependent release of an inhibitory peptide from the gamma-subunit.
2007,
Pubmed
,
Xenbase
Caldwell,
Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport.
2005,
Pubmed
Cavallo-Medved,
Caveolin-1 mediates the expression and localization of cathepsin B, pro-urokinase plasminogen activator and their cell-surface receptors in human colorectal carcinoma cells.
2005,
Pubmed
Coakley,
Abnormal surface liquid pH regulation by cultured cystic fibrosis bronchial epithelium.
2003,
Pubmed
Coote,
Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease.
2009,
Pubmed
Donaldson,
Regulation of the epithelial sodium channel by serine proteases in human airways.
2002,
Pubmed
,
Xenbase
El Khouri,
Functional interaction of the cystic fibrosis transmembrane conductance regulator with members of the SLC26 family of anion transporters (SLC26A8 and SLC26A9): physiological and pathophysiological relevance.
2014,
Pubmed
Gaillard,
Regulation of the epithelial Na+ channel and airway surface liquid volume by serine proteases.
2010,
Pubmed
Garcia-Caballero,
SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage.
2009,
Pubmed
,
Xenbase
Garland,
Molecular basis for pH-dependent mucosal dehydration in cystic fibrosis airways.
2013,
Pubmed
Garty,
Epithelial sodium channels: function, structure, and regulation.
1997,
Pubmed
Gentzsch,
The cystic fibrosis transmembrane conductance regulator impedes proteolytic stimulation of the epithelial Na+ channel.
2010,
Pubmed
Haerteis,
Proteolytic activation of the epithelial sodium channel (ENaC) by the cysteine protease cathepsin-S.
2012,
Pubmed
,
Xenbase
Harris,
Preferential assembly of epithelial sodium channel (ENaC) subunits in Xenopus oocytes: role of furin-mediated endogenous proteolysis.
2008,
Pubmed
,
Xenbase
Hartl,
Innate immunity in cystic fibrosis lung disease.
2012,
Pubmed
Harvey,
Measurement of the airway surface liquid volume with simple light refraction microscopy.
2011,
Pubmed
Hughey,
Maturation of the epithelial Na+ channel involves proteolytic processing of the alpha- and gamma-subunits.
2003,
Pubmed
,
Xenbase
Hughey,
Epithelial sodium channels are activated by furin-dependent proteolysis.
2004,
Pubmed
,
Xenbase
Jasti,
Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH.
2007,
Pubmed
Kerem,
Identification of the cystic fibrosis gene: genetic analysis.
1989,
Pubmed
Kesimer,
Tracheobronchial air-liquid interface cell culture: a model for innate mucosal defense of the upper airways?
2009,
Pubmed
Kleyman,
ENaC at the cutting edge: regulation of epithelial sodium channels by proteases.
2009,
Pubmed
Martin,
Association of airway cathepsin B and S with inflammation in cystic fibrosis.
2010,
Pubmed
Mirković,
Novel mechanism of cathepsin B inhibition by antibiotic nitroxoline and related compounds.
2011,
Pubmed
Moffitt,
Inflammatory and immunological biomarkers are not related to survival in adults with Cystic Fibrosis.
2014,
Pubmed
Moin,
Human tumour cathepsin B. Comparison with normal liver cathepsin B.
1992,
Pubmed
Myerburg,
Acute regulation of the epithelial sodium channel in airway epithelia by proteases and trafficking.
2010,
Pubmed
Naudin,
Human cysteine cathepsins are not reliable markers of infection by Pseudomonas aeruginosa in cystic fibrosis.
2011,
Pubmed
Orce,
Inhibition of short-circuit current in toad urinary bladder by inhibitors of glandular kallikrein.
1980,
Pubmed
Passero,
Defining an inhibitory domain in the gamma subunit of the epithelial sodium channel.
2010,
Pubmed
,
Xenbase
Pelletier,
Roles of divalent cations and pH in mechanism of action of nitroxoline against Escherichia coli strains.
1995,
Pubmed
Pezzulo,
Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung.
2012,
Pubmed
Planès,
In vitro and in vivo regulation of transepithelial lung alveolar sodium transport by serine proteases.
2005,
Pubmed
Poulsen,
Bicarbonate conductance and pH regulatory capability of cystic fibrosis transmembrane conductance regulator.
1994,
Pubmed
Quinton,
Role of epithelial HCO3⁻ transport in mucin secretion: lessons from cystic fibrosis.
2010,
Pubmed
Reddy,
Pericellular mobilization of the tissue-destructive cysteine proteinases, cathepsins B, L, and S, by human monocyte-derived macrophages.
1995,
Pubmed
Reiser,
Specialized roles for cysteine cathepsins in health and disease.
2010,
Pubmed
Riordan,
Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.
1989,
Pubmed
Roshy,
Pericellular cathepsin B and malignant progression.
2003,
Pubmed
Rozhin,
Properties of a plasma membrane-associated cathepsin B-like cysteine proteinase in metastatic B16 melanoma variants.
1987,
Pubmed
Rozhin,
Pericellular pH affects distribution and secretion of cathepsin B in malignant cells.
1994,
Pubmed
Sloane,
Cathepsin B: association with plasma membrane in metastatic tumors.
1986,
Pubmed
Sloane,
Plasma membrane-associated cysteine proteinases in human and animal tumors.
1987,
Pubmed
Sloane,
Membrane association of cathepsin B can be induced by transfection of human breast epithelial cells with c-Ha-ras oncogene.
1994,
Pubmed
Sloane,
Cathepsin B and tumor proteolysis: contribution of the tumor microenvironment.
2005,
Pubmed
Song,
Sodium and chloride concentrations, pH, and depth of airway surface liquid in distal airways.
2003,
Pubmed
Stutts,
Cystic fibrosis transmembrane conductance regulator inverts protein kinase A-mediated regulation of epithelial sodium channel single channel kinetics.
1997,
Pubmed
Tan,
Cleavage of endogenous γENaC and elevated abundance of αENaC are associated with increased Na⁺ transport in response to apical fluid volume expansion in human H441 airway epithelial cells.
2011,
Pubmed
Tarran,
Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion.
2013,
Pubmed
Tarran,
Soluble mediators, not cilia, determine airway surface liquid volume in normal and cystic fibrosis superficial airway epithelia.
2006,
Pubmed
Tong,
Prostasin, a membrane-anchored serine peptidase, regulates sodium currents in JME/CF15 cells, a cystic fibrosis airway epithelial cell line.
2004,
Pubmed
,
Xenbase
Yu,
Prostasin is a novel human serine proteinase from seminal fluid. Purification, tissue distribution, and localization in prostate gland.
1994,
Pubmed
