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Proteases, cystic fibrosis and the epithelial sodium channel (ENaC)

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Abstract

Proteases perform a diverse array of biological functions. From simple peptide digestion for nutrient absorption to complex signaling cascades, proteases are found in organisms from prokaryotes to humans. In the human airway, proteases are associated with the regulation of the airway surface liquid layer, tissue remodeling, host defense and pathogenic infection and inflammation. A number of proteases are released in the airways under both physiological and pathophysiological states by both the host and invading pathogens. In airway diseases such as cystic fibrosis, proteases have been shown to be associated with increased morbidity and airway disease progression. In this review, we focus on the regulation of proteases and discuss specifically those proteases found in human airways. Attention then shifts to the epithelial sodium channel (ENaC), which is regulated by proteolytic cleavage and that is considered to be an important component of cystic fibrosis disease. Finally, we discuss bacterial proteases, in particular, those of the most prevalent bacterial pathogen found in cystic fibrosis, Pseudomonas aeruginosa.

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References

  • Abu-El-Haija M, Sinkora M, Meyerholz DK, Welsh MJ, McCray PB Jr, Butler J, Uc A (2011) An activated immune and inflammatory response targets the pancreas of newborn pigs with cystic fibrosis. Pancreatology 11:506–515

    Article  PubMed  CAS  Google Scholar 

  • Adebamiro A, Johnson JP, Bridges RJ (2002) Aprotinin decreases the number of active Na+ channels in the apical membrane of A6 epithelia. Pediatr Pulmonol Suppl 24:211–212

    Google Scholar 

  • Adebamiro A, Cheng Y, Johnson JP, Bridges RJ (2005) Endogenous protease activation of ENaC: effect of serine protease inhibition on ENaC single channel properties. J Gen Physiol 126:339–352

    Article  PubMed  CAS  Google Scholar 

  • Adebamiro A, Cheng Y, Rao US, Danahay H, Bridges RJ (2007) A segment of gamma ENaC mediates elastase activation of Na+ transport. J Gen Physiol 130:611–629

    Article  PubMed  CAS  Google Scholar 

  • Azad AK, Rauh R, Vermeulen F, Jaspers M, Korbmacher J, Boissier B, Bassinet L, Fichou Y, Georges M des, Stanke F, De Boeck K, Dupont L, Balascakova M, Hjelte L, Lebecque P, Radojkovic D, Castellani C, Schwartz M, Stuhrmann M, Schwarz M, Skalicka V, Monestrol I de, Girodon E, Ferec C, Claustres M, Tummler B, Cassiman JJ, Korbmacher C, Cuppens H (2009) Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease. Hum Mutat 30:1093–1103

    Article  PubMed  CAS  Google Scholar 

  • Azghani AO, Baker JW, Shetty S, Miller EJ, Bhat GJ (2002) Pseudomonas aeruginosa elastase stimulates ERK signaling pathway and enhances IL-8 production by alveolar epithelial cells in culture. Inflamm Res 51:506–510

    Article  PubMed  CAS  Google Scholar 

  • Bainbridge T, Fick RB Jr (1989) Functional importance of cystic fibrosis immunoglobulin G fragments generated by Pseudomonas aeruginosa elastase. J Lab Clin Med 114:728–733

    PubMed  CAS  Google Scholar 

  • Baumann U (1994) Crystal structure of the 50 kDa metallo protease from Serratia marcescens. J Mol Biol 242:244–251

    Article  PubMed  CAS  Google Scholar 

  • Baumann U, Wu S, Flaherty KM, McKay DB (1993) Three-dimensional structure of the alkaline protease of Pseudomonas aeruginosa: a two-domain protein with a calcium binding parallel beta roll motif. EMBO J 12:3357–3364

    PubMed  CAS  Google Scholar 

  • Bens M, Chassin C, Vandewalle A (2006) Regulation of NaCl transport in the renal collecting duct: lessons from cultured cells. Pflugers Arch 453:133–146

    Article  PubMed  CAS  Google Scholar 

  • Bhalla V, Hallows KR (2008) Mechanisms of ENaC regulation and clinical implications. J Am Soc Nephrol 19:1845–1854

    Article  PubMed  CAS  Google Scholar 

  • Bosshart H, Humphrey J, Deignan E, Davidson J, Drazba J, Yuan L, Oorschot V, Peters PJ, Bonifacino JS (1994) The cytoplasmic domain mediates localization of furin to the trans-Golgi network en route to the endosomal/lysosomal system. J Cell Biol 126:1157–1172

    Article  PubMed  CAS  Google Scholar 

  • Boucher RC (2004) New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir J 23:146–158

    Article  PubMed  CAS  Google Scholar 

  • Briel M, Greger R, Kunzelmann K (1998) Cl- transport by cystic fibrosis transmembrane conductance regulator (CFTR) contributes to the inhibition of epithelial Na+ channels (ENaCs) in Xenopus oocytes co-expressing CFTR and ENaC. J Physiol 508:825–836

    Article  PubMed  CAS  Google Scholar 

  • Britigan BE, Hayek MB, Doebbeling BN, Fick RB Jr (1993) Transferrin and lactoferrin undergo proteolytic cleavage in the Pseudomonas aeruginosa-infected lungs of patients with cystic fibrosis. Infect Immun 61:5049–5055

    PubMed  CAS  Google Scholar 

  • Bruns JB, Carattino MD, Sheng S, Maarouf AB, Weisz OA, Pilewski JM, Hughey RP, Kleyman TR (2007) Epithelial Na+ channels are fully activated by furin- and prostasin-dependent release of an inhibitory peptide from the {gamma}-subunit. J Biol Chem 282:6153–6160

    Article  PubMed  CAS  Google Scholar 

  • Burke V, Robinson JO, Richardson CJ, Bundell CS (1991) Longitudinal studies of virulence factors of Pseudomonas aeruginosa in cystic fibrosis. Pathology 23:145–148

    Article  PubMed  CAS  Google Scholar 

  • Butterworth MB (2010) Regulation of the epithelial sodium channel (ENaC) by membrane trafficking. Biochim Biophys Acta 1802:1166–1177

    Article  PubMed  CAS  Google Scholar 

  • Butterworth MB, Edinger RS, Frizzell RA, Johnson JP (2009) Regulation of the epithelial sodium channel by membrane trafficking. Am J Physiol Renal Physiol 296:F10–F24

    Article  PubMed  CAS  Google Scholar 

  • Byrd MS, Pang B, Hong W, Waligora EA, Juneau RA, Armbruster CE, Weimer KE, Murrah K, Mann EE, Lu H, Sprinkle A, Parsek MR, Kock ND, Wozniak DJ, Swords WE (2011) Direct evaluation of Pseudomonas aeruginosa biofilm mediators in a chronic infection model. Infect Immun 79:3087–3095

    Article  PubMed  CAS  Google Scholar 

  • Caballero AR, Moreau JM, Engel LS, Marquart ME, Hill JM, O’Callaghan RJ (2001) Pseudomonas aeruginosa protease IV enzyme assays and comparison to other Pseudomonas proteases. Anal Biochem 290:330–337

    Article  PubMed  CAS  Google Scholar 

  • Caldwell RA, Boucher RC, Stutts MJ (2004) Serine protease activation of near-silent epithelial Na+ channels. Am J Physiol Cell Physiol 286:C190–C194

    Article  PubMed  CAS  Google Scholar 

  • Caldwell RA, Boucher RC, Stutts MJ (2005) Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport. Am J Physiol Lung Cell Mol Physiol 288:L813–L819

    Article  PubMed  CAS  Google Scholar 

  • Capasso G, Cantone A, Evangelista C, Zacchia M, Trepiccione F, Acone D, Rizzo M (2005) Channels, carriers, and pumps in the pathogenesis of sodium-sensitive hypertension. Semin Nephrol 25:419–424

    Article  PubMed  CAS  Google Scholar 

  • Carattino MD, Passero CJ, Steren CA, Maarouf AB, Pilewski JM, Myerburg MM, Hughey RP, Kleyman TR (2008) Defining an inhibitory domain in the alpha-subunit of the epithelial sodium channel. Am J Physiol Renal Physiol 294:F47–F52

    Article  PubMed  CAS  Google Scholar 

  • Chambers LA, Rollins BM, Tarran R (2007) Liquid movement across the surface epithelium of large airways. Respir Physiol Neurobiol 159:256–270

    Article  PubMed  CAS  Google Scholar 

  • Chen JH, Stoltz DA, Karp PH, Ernst SE, Pezzulo AA, Moninger TO, Rector MV, Reznikov LR, Launspach JL, Chaloner K, Zabner J, Welsh MJ (2010) Loss of anion transport without increased sodium absorption characterizes newborn porcine cystic fibrosis airway epithelia. Cell 143:911–923

    Article  PubMed  CAS  Google Scholar 

  • Cheng SH, Rich DP, Marshall J, Gregory RJ, Welsh MJ, Smith AE (1991) Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel. Cell 66:1027–1036

    Article  PubMed  CAS  Google Scholar 

  • Choi JY, Muallem D, Kiselyov K, Lee MG, Thomas PJ, Muallem S (2001) Aberrant CFTR-dependent HCO3 - transport in mutations associated with cystic fibrosis. Nature 410:94–97

    Article  PubMed  CAS  Google Scholar 

  • Chow SC, Weis M, Kass GE, Holmstrom TH, Eriksson JE, Orrenius S (1995) Involvement of multiple proteases during Fas-mediated apoptosis in T lymphocytes. FEBS Lett 364:134–138

    Article  PubMed  CAS  Google Scholar 

  • Ciechanover A (1998) The ubiquitin-proteasome pathway: on protein death and cell life. EMBO J 17:7151–7160

    Article  PubMed  CAS  Google Scholar 

  • Conese M, Copreni E, Di Gioia S, De Rinaldis P, Fumarulo R (2003) Neutrophil recruitment and airway epithelial cell involvement in chronic cystic fibrosis lung disease. J Cyst Fibros 2:129–135

    Article  PubMed  CAS  Google Scholar 

  • Coraux C, Roux J, Jolly T, Birembaut P (2008) Epithelial cell-extracellular matrix interactions and stem cells in airway epithelial regeneration. Proc Am Thorac Soc 5:689–694

    Article  PubMed  Google Scholar 

  • Cottrell GS, Amadesi S, Grady EF, Bunnett NW (2004) Trypsin IV, a novel agonist of protease-activated receptors 2 and 4. J Biol Chem 279:13532–13539

    Article  PubMed  CAS  Google Scholar 

  • Dean M, Hamon Y, Chimini G (2001) The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res 42:1007–1017

    PubMed  CAS  Google Scholar 

  • Di Cera E, Cantwell AM (2001) Determinants of thrombin specificity. Ann N Y Acad Sci 936:133–146

    Article  PubMed  Google Scholar 

  • Donaldson SH, Hirsh A, Li DC, Holloway G, Chao J, Boucher RC, Gabriel SE (2002) Regulation of the epithelial sodium channel by serine proteases in human airways. J Biol Chem 277:8338–8345

    Article  PubMed  CAS  Google Scholar 

  • Downey DG, Brockbank S, Martin SL, Ennis M, Elborn JS (2007a) The effect of treatment of cystic fibrosis pulmonary exacerbations on airways and systemic inflammation. Pediatr Pulmonol 42:729–735

    Article  PubMed  Google Scholar 

  • Downey DG, Martin SL, Dempster M, Moore JE, Keogan MT, Starcher B, Edgar J, Bilton D, Elborn JS (2007b) The relationship of clinical and inflammatory markers to outcome in stable patients with cystic fibrosis. Pediatr Pulmonol 42:216–220

    Article  PubMed  Google Scholar 

  • Downey DG, Bell SC, Elborn JS (2009) Neutrophils in cystic fibrosis. Thorax 64:81–88

    Article  PubMed  CAS  Google Scholar 

  • Drumm ML, Pope HA, Cliff WH, Rommens JM, Marvin SA, Tsui LC, Collins FS, Frizzell RA, Wilson JM (1990) Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer. Cell 62:1227–1233

    Article  PubMed  CAS  Google Scholar 

  • Duong F, Lazdunski A, Cami B, Murgier M (1992) Sequence of a cluster of genes controlling synthesis and secretion of alkaline protease in Pseudomonas aeruginosa: relationships to other secretory pathways. Gene 121:47–54

    Article  PubMed  CAS  Google Scholar 

  • Eaton DC, Helms MN, Koval M, Bao HF, Jain L (2009) The contribution of epithelial sodium channels to alveolar function in health and disease. Annu Rev Physiol 71:403–423

    Article  PubMed  CAS  Google Scholar 

  • Ecelbarger CA, Tiwari S (2006) Sodium transporters in the distal nephron and disease implications. Curr Hypertens Rep 8:158–165

    Article  PubMed  CAS  Google Scholar 

  • Edelheit O, Hanukoglu I, Gizewska M, Kandemir N, Tenenbaum-Rakover Y, Yurdakok M, Zajaczek S, Hanukoglu A (2005) Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism. Clin Endocrinol 62:547–553

    Article  CAS  Google Scholar 

  • Egnell P, Flock JI (1992) The autocatalytic processing of the subtilisin Carlsberg pro-region is independent of the primary structure of the cleavage site. Mol Microbiol 6:1115–1119

    Article  PubMed  CAS  Google Scholar 

  • Elizur A, Cannon CL, Ferkol TW (2008) Airway inflammation in cystic fibrosis. Chest 133:489–495

    Article  PubMed  Google Scholar 

  • Engel LS, Hobden JA, Moreau JM, Callegan MC, Hill JM, O’Callaghan RJ (1997) Pseudomonas deficient in protease IV has significantly reduced corneal virulence. Invest Ophthalmol Vis Sci 38:1535–1542

    PubMed  CAS  Google Scholar 

  • Engel LS, Hill JM, Caballero AR, Green LC, O’Callaghan RJ (1998) Protease IV, a unique extracellular protease and virulence factor from Pseudomonas aeruginosa. J Biol Chem 273:16792–16797

    Article  PubMed  CAS  Google Scholar 

  • Erez E, Fass D, Bibi E (2009) How intramembrane proteases bury hydrolytic reactions in the membrane. Nature 459:371–378

    Article  PubMed  CAS  Google Scholar 

  • Ergonul Z, Frindt G, Palmer LG (2006) Regulation of maturation and processing of ENaC subunits in the rat kidney. Am J Physiol Renal Physiol 291:F683–F693

    Article  PubMed  CAS  Google Scholar 

  • Fleiszig SM, Evans DJ, Do N, Vallas V, Shin S, Mostov KE (1997) Epithelial cell polarity affects susceptibility to Pseudomonas aeruginosa invasion and cytotoxicity. Infect Immun 65:2861–2867

    PubMed  CAS  Google Scholar 

  • Freundlich M, Ludwig M (2005) A novel epithelial sodium channel beta-subunit mutation associated with hypertensive Liddle syndrome. Pediatr Nephrol 20:512–515

    Article  PubMed  Google Scholar 

  • Fritz LC, Haidar MA, Arfsten AE, Schilling JW, Carilli C, Shine J, Baxter JD, Reudelhuber TL (1987) Human renin is correctly processed and targeted to the regulated secretory pathway in mouse pituitary AtT-20 cells. J Biol Chem 262:12409–12412

    PubMed  CAS  Google Scholar 

  • Gaillard EA, Kota P, Gentzsch M, Dokholyan NV, Stutts MJ, Tarran R (2010) Regulation of the epithelial Na+ channel and airway surface liquid volume by serine proteases. Pflugers Arch 460:1–17

    Article  PubMed  CAS  Google Scholar 

  • Goldberg JB, Ohman DE (1987) Cloning and transcriptional regulation of the elastase lasA gene in mucoid and nonmucoid Pseudomonas aeruginosa. J Bacteriol 169:1349–1351

    PubMed  CAS  Google Scholar 

  • Gormley K, Dong Y, Sagnella GA (2003) Regulation of the epithelial sodium channel by accessory proteins. Biochem J 371:1–14

    Article  PubMed  CAS  Google Scholar 

  • Gorogh T, Beier UH, Baumken J, Meyer JE, Hoffmann M, Gottschlich S, Maune S (2006) Metalloproteinases and their inhibitors: influence on tumor invasiveness and metastasis formation in head and neck squamous cell carcinomas. Head Neck 28:31–39

    Article  PubMed  Google Scholar 

  • Granstrom M, Ericsson A, Strandvik B, Wretlind B, Pavlovskis OR, Berka R, Vasil ML (1984) Relation between antibody response to Pseudomonas aeruginosa exoproteins and colonization/infection in patients with cystic fibrosis. Acta Paediatr Scand 73:772–777

    Article  PubMed  CAS  Google Scholar 

  • Gregory RJ, Cheng SH, Rich DP, Marshall J, Paul S, Hehir K, Ostedgaard L, Klinger KW, Welsh MJ, Smith AE (1990) Expression and characterization of the cystic fibrosis transmembrane conductance regulator. Nature 347:382–386

    Article  PubMed  CAS  Google Scholar 

  • Griese M, Kappler M, Gaggar A, Hartl D (2008) Inhibition of airway proteases in cystic fibrosis lung disease. Eur Respir J 32:783–795

    Article  PubMed  CAS  Google Scholar 

  • Guyot N, Butler MW, McNally P, Weldon S, Greene CM, Levine RL, O’Neill SJ, Taggart CC, McElvaney NG (2008) Elafin, an elastase-specific inhibitor, is cleaved by its cognate enzyme neutrophil elastase in sputum from individuals with cystic fibrosis. J Biol Chem 283:32377–32385

    Article  PubMed  CAS  Google Scholar 

  • Guyot N, Bergsson G, Butler MW, Greene CM, Weldon S, Kessler E, Levine RL, O’Neill SJ, Taggart CC, McElvaney NG (2010) Functional study of elafin cleaved by Pseudomonas aeruginosa metalloproteinases. Biol Chem 391:705–716

    Article  PubMed  CAS  Google Scholar 

  • Guzzo J, Murgier M, Filloux A, Lazdunski A (1990) Cloning of the Pseudomonas aeruginosa alkaline protease gene and secretion of the protease into the medium by Escherichia coli. J Bacteriol 172:942–948

    PubMed  CAS  Google Scholar 

  • Hamm LL, Feng Z, Hering-Smith KS (2010) Regulation of sodium transport by ENaC in the kidney. Curr Opin Nephrol Hypertens 19:98–105

    Article  PubMed  CAS  Google Scholar 

  • Harris M, Garcia-Caballero A, Stutts MJ, Firsov D, Rossier BC (2008) Preferential assembly of ENaC subunits in Xenopus oocyte: role of furin-mediated endogenous proteolysis. J Biol Chem 283:7455–7463

    Article  PubMed  CAS  Google Scholar 

  • Heck LW, Alarcon PG, Kulhavy RM, Morihara K, Russell MW, Mestecky JF (1990) Degradation of IgA proteins by Pseudomonas aeruginosa elastase. J Immunol 144:2253–2257

    PubMed  CAS  Google Scholar 

  • Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479

    Article  PubMed  CAS  Google Scholar 

  • Hobden JA (2002) Pseudomonas aeruginosa proteases and corneal virulence. DNA Cell Biol 21:391–396

    Article  PubMed  CAS  Google Scholar 

  • Hopf A, Schreiber R, Mall M, Greger R, Kunzelmann K (1999) Cystic fibrosis transmembrane conductance regulator inhibits epithelial Na+ channels carrying Liddle’s syndrome mutations. J Biol Chem 274:13894–13899

    Article  PubMed  CAS  Google Scholar 

  • Horvat RT, Clabaugh M, Duval-Jobe C, Parmely MJ (1989) Inactivation of human gamma interferon by Pseudomonas aeruginosa proteases: elastase augments the effects of alkaline protease despite the presence of alpha 2-macroglobulin. Infect Immun 57:1668–1674

    PubMed  CAS  Google Scholar 

  • Huber R, Krueger B, Diakov A, Korbmacher J, Haerteis S, Einsiedel J, Gmeiner P, Azad AK, Cuppens H, Cassiman JJ, Korbmacher C, Rauh R (2010) Functional characterization of a partial loss-of-function mutation of the epithelial sodium channel (ENaC) associated with atypical cystic fibrosis. Cell Physiol Biochem 25:145–158

    Article  PubMed  CAS  Google Scholar 

  • Hughey RP, Mueller GM, Bruns JB, Kinlough CL, Poland PA, Harkleroad KL, Carattino MD, Kleyman TR (2003) Maturation of the epithelial Na+ channel involves proteolytic processing of the alpha- and gamma-subunits. J Biol Chem 278:37073–37082

    Article  PubMed  CAS  Google Scholar 

  • Hughey RP, Bruns JB, Kinlough CL, Harkleroad KL, Tong Q, Carattino MD, Johnson JP, Stockand JD, Kleyman TR (2004a) Epithelial sodium channels are activated by furin-dependent proteolysis. J Biol Chem 279:18111–18114

    Article  PubMed  CAS  Google Scholar 

  • Hughey RP, Bruns JB, Kinlough CL, Kleyman TR (2004b) Distinct pools of epithelial sodium channels are expressed at the plasma membrane. J Biol Chem 279:48491–48494

    Article  PubMed  CAS  Google Scholar 

  • Hughey RP, Carattino MD, Kleyman TR (2007) Role of proteolysis in the activation of epithelial sodium channels. Curr Opin Nephrol Hypertens 16:444–450

    Article  PubMed  CAS  Google Scholar 

  • Hummler E (1999) Implication of ENaC in salt-sensitive hypertension. J Steroid Biochem Mol Biol 69:385–390

    Article  PubMed  CAS  Google Scholar 

  • Itani OA, Chen JH, Karp PH, Ernst S, Keshavjee S, Parekh K, Klesney-Tait J, Zabner J, Welsh MJ (2011) Human cystic fibrosis airway epithelia have reduced Cl- conductance but not increased Na+ conductance. Proc Natl Acad Sci USA 108:10260–10265

    Article  PubMed  CAS  Google Scholar 

  • Jagger KS, Robinson DL, Franz MN, Warren RL (1982) Detection by enzyme-linked immunosorbent assays of antibody specific for Pseudomonas proteases and exotoxin A in sera from cystic fibrosis patients. J Clin Microbiol 15:1054–1058

    PubMed  CAS  Google Scholar 

  • Jagger KS, Bahner DR, Warren RL (1983) Protease phenotypes of Pseudomonas aeruginosa isolated from patients with cystic fibrosis. J Clin Microbiol 17:55–59

    PubMed  CAS  Google Scholar 

  • Ji HL, Chalfant ML, Jovov B, Lockhart JP, Parker SB, Fuller CM, Stanton BA, Benos DJ (2000) The cytosolic termini of the beta- and gamma-ENaC subunits are involved in the functional interactions between cystic fibrosis transmembrane conductance regulator and epithelial sodium channel. J Biol Chem 275:27947–27956

    PubMed  CAS  Google Scholar 

  • Jiang Q, Li J, Dubroff R, Ahn YJ, Foskett JK, Engelhardt J, Kleyman TR (2000) Epithelial sodium channels regulate cystic fibrosis transmembrane conductance regulator chloride channels in Xenopus oocytes. J Biol Chem 275:13266–13274

    Article  PubMed  CAS  Google Scholar 

  • Johnson GG, Morris JM, Berk RS (1967) The extracellular protease from Pseudomonas aeruginosa exhibiting elastase activity. Can J Microbiol 13:711–719

    Article  PubMed  CAS  Google Scholar 

  • Kametaka S, Shibata M, Moroe K, Kanamori S, Ohsawa Y, Waguri S, Sims PJ, Emoto K, Umeda M, Uchiyama Y (2003) Identification of phospholipid scramblase 1 as a novel interacting molecule with beta-secretase (beta-site amyloid precursor protein (APP) cleaving enzyme (BACE)). J Biol Chem 278:15239–15245

    Article  PubMed  CAS  Google Scholar 

  • Kent G, Iles R, Bear CE, Huan LJ, Griesenbach U, McKerlie C, Frndova H, Ackerley C, Gosselin D, Radzioch D, O’Brodovich H, Tsui LC, Buchwald M, Tanswell AK (1997) Lung disease in mice with cystic fibrosis. J Clin Invest 100:3060–3069

    Article  PubMed  CAS  Google Scholar 

  • Kercsmar CM, Davis PB (1993) Resistance of human tracheal epithelial cells to killing by neutrophils, neutrophil elastase, and Pseudomonas elastase. Am J Respir Cell Mol Biol 8:56–62

    PubMed  CAS  Google Scholar 

  • Kessler E, Safrin M (1988) Partial purification and characterization of an inactive precursor of Pseudomonas aeruginosa elastase. J Bacteriol 170:1215–1219

    PubMed  CAS  Google Scholar 

  • Kessler E, Safrin M (1994) The propeptide of Pseudomonas aeruginosa elastase acts an elastase inhibitor. J Biol Chem 269:22726–22731

    PubMed  CAS  Google Scholar 

  • Kessler E, Safrin M, Olson JC, Ohman DE (1993) Secreted LasA of Pseudomonas aeruginosa is a staphylolytic protease. J Biol Chem 268:7503–7508

    PubMed  Google Scholar 

  • Kessler E, Safrin M, Gustin JK, Ohman DE (1998) Elastase and the LasA protease of Pseudomonas aeruginosa are secreted with their propeptides. J Biol Chem 273:30225–30231

    Article  PubMed  CAS  Google Scholar 

  • Kharazmi A, Doring G, Hoiby N, Valerius NH (1984a) Interaction of Pseudomonas aeruginosa alkaline protease and elastase with human polymorphonuclear leukocytes in vitro. Infect Immun 43:161–165

    PubMed  CAS  Google Scholar 

  • Kharazmi A, Hoiby N, Doring G, Valerius NH (1984b) Pseudomonas aeruginosa exoproteases inhibit human neutrophil chemiluminescence. Infect Immun 44:587–591

    PubMed  CAS  Google Scholar 

  • Kleyman TR, Myerburg MM, Hughey RP (2006) Regulation of ENaCs by proteases: an increasingly complex story. Kidney Int 70:1391–1392

    Article  PubMed  CAS  Google Scholar 

  • Kleyman TR, Carattino MD, Hughey RP (2009) ENaC at the cutting edge: regulation of epithelial sodium channels by proteases. J Biol Chem 284:20447–20451

    Article  PubMed  CAS  Google Scholar 

  • Ko SB, Shcheynikov N, Choi JY, Luo X, Ishibashi K, Thomas PJ, Kim JY, Kim KH, Lee MG, Naruse S, Muallem S (2002) A molecular mechanism for aberrant CFTR-dependent HCO3 − transport in cystic fibrosis. EMBO J 21:5662–5672

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi H (2005) Airway biofilms: implications for pathogenesis and therapy of respiratory tract infections. Treat Respir Med 4:241–253

    Article  PubMed  CAS  Google Scholar 

  • Kudoh I, Wiener-Kronish JP, Hashimoto S, Pittet JF, Frank D (1994) Exoproduct secretions of Pseudomonas aeruginosa strains influence severity of alveolar epithelial injury. Am J Physiol 267:L551–L556

    PubMed  CAS  Google Scholar 

  • Kunzelmann K, Kiser GL, Schreiber R, Riordan JR (1997) Inhibition of epithelial Na+ currents by intracellular domains of the cystic fibrosis transmembrane conductance regulator. FEBS Lett 400:341–344

    Article  PubMed  CAS  Google Scholar 

  • Lang F, Huang DY, Vallon V (2010) SGK, renal function and hypertension. J Nephrol 23 (Suppl 16):S124–S129

    PubMed  Google Scholar 

  • Lazdunski A, Guzzo J, Filloux A, Bally M, Murgier M (1990) Secretion of extracellular proteins by Pseudomonas aeruginosa. Biochimie 72:147–156

    Article  PubMed  CAS  Google Scholar 

  • Lee B, Schjerling CK, Kirkby N, Hoffmann N, Borup R, Molin S, Hoiby N, Ciofu O (2011) Mucoid Pseudomonas aeruginosa isolates maintain the biofilm formation capacity and the gene expression profiles during the chronic lung infection of CF patients. APMIS 119:263–274

    Article  PubMed  Google Scholar 

  • Leidal KG, Munson KL, Johnson MC, Denning GM (2003) Metalloproteases from Pseudomonas aeruginosa degrade human RANTES, MCP-1, and ENA-78. J Interferon Cytokine Res 23:307–318

    Article  PubMed  CAS  Google Scholar 

  • Levene PA (1905) The cleavage of products of proteoses. J Biol Chem 1:45–58

    Google Scholar 

  • Li J, Wang DH (2007) Function and regulation of epithelial sodium transporters in the kidney of a salt-sensitive hypertensive rat model. J Hypertens 25:1065–1072

    Article  PubMed  CAS  Google Scholar 

  • Liu L, Hering-Smith KS, Schiro FR, Hamm LL (2002) Serine protease activity in m-1 cortical collecting duct cells. Hypertension 39:860–864

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Otin C, Bond JS (2008) Proteases: multifunctional enzymes in life and disease. J Biol Chem 283:30433–30437

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Otin C, Matrisian LM (2007) Emerging roles of proteases in tumour suppression. Nat Rev Cancer 7:800–808

    Article  PubMed  CAS  Google Scholar 

  • Louis D, Bernillon J, Wallach JM (1998) Specificity of Pseudomonas aeruginosa serralysin revisited, using biologically active peptides as substrates. Biochim Biophys Acta 1387:378–386

    Article  PubMed  CAS  Google Scholar 

  • Lyczak JB, Cannon CL, Pier GB (2000) Establishment of Pseudomonas aeruginosa infection: lessons from a versatile opportunist. Microbes Infect 2:1051–1060

    Article  PubMed  CAS  Google Scholar 

  • Lyczak JB, Cannon CL, Pier GB (2002) Lung infections associated with cystic fibrosis. Clin Microbiol Rev 15:194–222

    Article  PubMed  CAS  Google Scholar 

  • Mall MA (2008) Role of cilia, mucus, and airway surface liquid in mucociliary dysfunction: lessons from mouse models. J Aerosol Med Pulm Drug Deliv 21:13–24

    Article  PubMed  CAS  Google Scholar 

  • Mall M, Bleich M, Kuehr J, Brandis M, Greger R, Kunzelmann K (1999) CFTR-mediated inhibition of epithelial Na+ conductance in human colon is defective in cystic fibrosis. Am J Physiol 277:G709–G716

    PubMed  CAS  Google Scholar 

  • Mall M, Grubb BR, Harkema JR, O’Neal WK, Boucher RC (2004) Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat Med 10:487–493

    Article  PubMed  CAS  Google Scholar 

  • Malloy JL, Veldhuizen RA, Thibodeaux BA, O’Callaghan RJ, Wright JR (2005) Pseudomonas aeruginosa protease IV degrades surfactant proteins and inhibits surfactant host defense and biophysical functions. Am J Physiol Lung Cell Mol Physiol 288:L409–L418

    Article  PubMed  CAS  Google Scholar 

  • Manos J, Arthur J, Rose B, Tingpej P, Fung C, Curtis M, Webb JS, Hu H, Kjelleberg S, Gorrell MD, Bye P, Harbour C (2008) Transcriptome analyses and biofilm-forming characteristics of a clonal seudomonas aeruginosa from the cystic fibrosis lung. J Med Microbiol 57:1454–1465

    Article  PubMed  CAS  Google Scholar 

  • Manos J, Arthur J, Rose B, Bell S, Tingpej P, Hu H, Webb J, Kjelleberg S, Gorrell MD, Bye P, Harbour C (2009) Gene expression characteristics of a cystic fibrosis epidemic strain of Pseudomonas aeruginosa during biofilm and planktonic growth. FEMS Microbiol Lett 292:107–114

    Article  PubMed  CAS  Google Scholar 

  • Mariencheck WI, Alcorn JF, Palmer SM, Wright JR (2003) Pseudomonas aeruginosa elastase degrades surfactant proteins A and D. Am J Respir Cell Mol Biol 28:528–537

    Article  PubMed  CAS  Google Scholar 

  • Marino CR, Matovcik LM, Gorelick FS, Cohn JA (1991) Localization of the cystic fibrosis transmembrane conductance regulator in pancreas. J Clin Invest 88:712–716

    Article  PubMed  CAS  Google Scholar 

  • Matthay MA, Robriquet L, Fang X (2005) Alveolar epithelium: role in lung fluid balance and acute lung injury. Proc Am Thorac Soc 2:206–213

    Article  PubMed  CAS  Google Scholar 

  • Mirghomizadeh F, Bullwinkel J, Orinska Z, Janssen O, Petersen A, Singh PB, Bulfone-Paus S (2009) Transcriptional regulation of mouse mast cell protease-2 by interleukin-15. J Biol Chem 284:32635–32641

    Article  PubMed  CAS  Google Scholar 

  • Mossessova E, Lima CD (2000) Ulp1-SUMO crystal structure and genetic analysis reveal conserved interactions and a regulatory element essential for cell growth in yeast. Mol Cell 5:865–876

    Article  PubMed  CAS  Google Scholar 

  • Muzio M, Salvesen GS, Dixit VM (1997) FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens. J Biol Chem 272:2952–2956

    Article  PubMed  CAS  Google Scholar 

  • Myerburg MM, Butterworth MB, McKenna EE, Peters KW, Frizzell RA, Kleyman TR, Pilewski JM (2006) Airway surface liquid volume regulates ENaC by altering the serine protease-protease inhibitor balance: a mechanism for sodium hyperabsorption in cystic fibrosis. J Biol Chem 281:27942–27949

    Article  PubMed  CAS  Google Scholar 

  • Myerburg MM, Harvey PR, Heidrich EM, Pilewski JM, Butterworth MB (2010) Acute regulation of the epithelial sodium channel in airway epithelia by proteases and trafficking. Am J Respir Cell Mol Biol 43:712–719

    Article  PubMed  CAS  Google Scholar 

  • O’Callaghan RJ, Engel LS, Hobden JA, Callegan MC, Green LC, Hill JM (1996) Pseudomonas keratitis. The role of an uncharacterized exoprotein, protease IV, in corneal virulence. Invest Ophthalmol Vis Sci 37:534–543

    PubMed  Google Scholar 

  • Oda K (2012) New families of carboxyl peptidases: serine-carboxyl peptidases and glutamic peptidases. J Biochem 151:13–25

    Article  PubMed  CAS  Google Scholar 

  • Orce GG, Castillo GA, Margolius HS (1980) Inhibition of short-circuit current in toad urinary bladder by inhibitors of glandular kallikrein. Am J Physiol 239:F459–F465

    PubMed  CAS  Google Scholar 

  • Orce GG, Castillo GA, Margolius HS (1981) Kallikrein inhibitors decrease short-circuit current by inhibiting sodium uptake. Hypertension 3:92–95

    CAS  Google Scholar 

  • Overall CM, Tam EM, Kappelhoff R, Connor A, Ewart T, Morrison CJ, Puente X, Lopez-Otin C, Seth A (2004) Protease degradomics: mass spectrometry discovery of protease substrates and the CLIP-CHIP, a dedicated DNA microarray of all human proteases and inhibitors. Biol Chem 385:493–504

    Article  PubMed  CAS  Google Scholar 

  • Parmely MJ, Horvat RT (1986) Antigenic specificities of seudomonas aeruginosa alkaline protease and elastase defined by human T cell clones. J Immunol 137:988–994

    PubMed  CAS  Google Scholar 

  • Parmely MJ, Iglewski BH, Horvat RT (1984) Identification of the principal T lymphocyte-stimulating antigens of Pseudomonas aeruginosa. J Exp Med 160:1338–1349

    Article  PubMed  CAS  Google Scholar 

  • Parmely MJ, Horvat RT, Iglewski BH, Kanarek J, Furtado D, Van Enk R (1987) The antigenicity of a pulmonary pathogen defined by monoclonal T cells. Adv Exp Med Biol 216B:1043–1051

    PubMed  CAS  Google Scholar 

  • Parmely M, Gale A, Clabaugh M, Horvat R, Zhou WW (1990) Proteolytic inactivation of cytokines by Pseudomonas aeruginosa. Infect Immun 58:3009–3014

    PubMed  CAS  Google Scholar 

  • Passero CJ, Mueller GM, Rondon-Berrios H, Tofovic SP, Hughey RP, Kleyman TR (2008) Plasmin activates epithelial Na+ channels by cleaving the gamma subunit. J Biol Chem 283:36586–36591

    Article  PubMed  CAS  Google Scholar 

  • Planes C, Caughey GH (2007) Regulation of the epithelial Na+ channel by peptidases. Curr Top Dev Biol 78:23–46

    Article  PubMed  CAS  Google Scholar 

  • Planes C, Leyvraz C, Uchida T, Angelova MA, Vuagniaux G, Hummler E, Matthay M, Clerici C, Rossier B (2005) In vitro and in vivo regulation of transepithelial lung alveolar sodium transport by serine proteases. Am J Physiol Lung Cell Mol Physiol 288:L1099–L1109

    Article  PubMed  CAS  Google Scholar 

  • Pochynyuk O, Tong Q, Staruschenko A, Ma HP, Stockand JD (2006) Regulation of the epithelial Na+ channel (ENaC) by phosphatidylinositides. Am J Physiol Renal Physiol 290:F949–F957

    Article  PubMed  CAS  Google Scholar 

  • Puente XS, Sanchez LM, Overall CM, Lopez-Otin C (2003) Human and mouse proteases: a comparative genomic approach. Nat Rev Genet 4:544–558

    Article  PubMed  CAS  Google Scholar 

  • Quesada V, Ordonez GR, Sanchez LM, Puente XS, Lopez-Otin C (2009) The Degradome database: mammalian proteases and diseases of proteolysis. Nucleic Acids Res 37:D239–D243

    Article  PubMed  CAS  Google Scholar 

  • Rauh R, Diakov A, Tzschoppe A, Korbmacher J, Azad AK, Cuppens H, Cassiman JJ, Dotsch J, Sticht H, Korbmacher C (2010) A mutation of the epithelial sodium channel associated with atypical cystic fibrosis increases channel open probability and reduces Na+ self inhibition. J Physiol 588:1211–1225

    Article  PubMed  CAS  Google Scholar 

  • Ravaud S, Gouet P, Haser R, Aghajari N (2003) Probing the role of divalent metal ions in a bacterial psychrophilic metalloprotease: binding studies of an enzyme in the crystalline state by X-ray crystallography. J Bacteriol 185:4195–4203

    Article  PubMed  CAS  Google Scholar 

  • Rawlings ND, Barrett AJ, Bateman A (2010) MEROPS: the peptidase database. Nucleic Acids Res 38:D227–D233

    Article  PubMed  CAS  Google Scholar 

  • Rawlings ND, Barrett AJ, Bateman A (2012) MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res 40:D343–D350

    Article  PubMed  CAS  Google Scholar 

  • Reddy MM, Quinton PM (2003) Functional interaction of CFTR and ENaC in sweat glands. Pflugers Arch 445:499–503

    PubMed  CAS  Google Scholar 

  • Reddy MM, Light MJ, Quinton PM (1999) Activation of the epithelial Na+ channel (ENaC) requires CFTR Cl- channel function. Nature 402:301–304

    Article  PubMed  CAS  Google Scholar 

  • Reeves EP, McElvaney NG (2012) The facilitating effect of hypertonic saline on resolution of airway inflammation in cystic fibrosis. Am J Respir Crit Care Med 185:226–227

    PubMed  Google Scholar 

  • Rich DP, Anderson MP, Gregory RJ, Cheng SH, Paul S, Jefferson DM, McCann JD, Klinger KW, Smith AE, Welsh MJ (1990) Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature 347:358–363

    Article  PubMed  CAS  Google Scholar 

  • Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL et al (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–1073

    Article  PubMed  CAS  Google Scholar 

  • Rollins BM, Garcia-Caballero A, Stutts MJ, Tarran R (2010) SPLUNC1 expression reduces surface levels of the epithelial sodium channel (ENaC) in Xenopus laevis oocytes. Channels (Austin) 4:255–259

    Article  CAS  Google Scholar 

  • Rossier BC (2002) Hormonal regulation of the epithelial sodium channel ENaC: N or Po? J Gen Physiol 120:67–70

    Article  PubMed  CAS  Google Scholar 

  • Rossier BC (2004) The epithelial sodium channel: activation by membrane-bound serine proteases. Proc Am Thorac Soc 1:4–9

    Article  PubMed  CAS  Google Scholar 

  • Rossier BC, Stutts MJ (2009) Activation of the epithelial sodium channel (ENaC) by serine proteases. Annu Rev Physiol 71:361–379

    Article  PubMed  CAS  Google Scholar 

  • Rust L, Pesci EC, Iglewski BH (1996) Analysis of the Pseudomonas aeruginosa elastase (lasB) regulatory region. J Bacteriol 178:1134–1140

    PubMed  CAS  Google Scholar 

  • Saadane A, Soltys J, Berger M (2006) Acute Pseudomonas challenge in cystic fibrosis mice causes prolonged nuclear factor-kappa B activation, cytokine secretion, and persistent lung inflammation. J Allergy Clin Immunol 117:1163–1169

    Article  PubMed  CAS  Google Scholar 

  • Sagel SD, Sontag MK, Wagener JS, Kapsner RK, Osberg I, Accurso FJ (2002) Induced sputum inflammatory measures correlate with lung function in children with cystic fibrosis. J Pediatr 141:811–817

    Article  PubMed  Google Scholar 

  • Salunkhe P, Smart CH, Morgan JA, Panagea S, Walshaw MJ, Hart CA, Geffers R, Tummler B, Winstanley C (2005) A cystic fibrosis epidemic strain of Pseudomonas aeruginosa displays enhanced virulence and antimicrobial resistance. J Bacteriol 187:4908–4920

    Article  PubMed  CAS  Google Scholar 

  • Salvesen GS, Riedl SJ (2008) Caspase mechanisms. Adv Exp Med Biol 615:13–23

    Article  PubMed  CAS  Google Scholar 

  • Sarkisova S, Patrauchan MA, Berglund D, Nivens DE, Franklin MJ (2005a) Calcium-induced virulence factors associated with the extracellular matrix of mucoid Pseudomonas aeruginosa biofilms. J Bacteriol 187:4327–4337

    Article  PubMed  CAS  Google Scholar 

  • Sarkisova S, Patrauchan MA, Berglund D, Nivens DE, Franklin MJ (2005b) Calcium-induced virulence factors associated with the extracellular matrix of mucoid Pseudomonas aeruginosa biofilms. J Bacteriol 187:4327–4337

    Article  PubMed  CAS  Google Scholar 

  • Saulnier JM, Curtil FM, Duclos MC, Wallach JM (1989) Elastolytic activity of Pseudomonas aeruginosa elastase. Biochim Biophys Acta 995:285–290

    Article  PubMed  CAS  Google Scholar 

  • Schafer W, Stroh A, Berghofer S, Seiler J, Vey M, Kruse ML, Kern HF, Klenk HD, Garten W (1995) Two independent targeting signals in the cytoplasmic domain determine trans-Golgi network localization and endosomal trafficking of the proprotein convertase furin. EMBO J 14:2424–2435

    PubMed  CAS  Google Scholar 

  • Schreiber R, Hopf A, Mall M, Greger R, Kunzelmann K (1999) The first-nucleotide binding domain of the cystic-fibrosis transmembrane conductance regulator is important for inhibition of the epithelial Na+ channel. Proc Natl Acad Sci USA 96:5310–5315

    Article  PubMed  CAS  Google Scholar 

  • Sheng S, Carattino MD, Bruns JB, Hughey RP, Kleyman TR (2006) Furin cleavage activates the epithelial Na+ channels by relieving Na+ self-inhibition. Am J Physiol Renal Physiol 290:F1488–F1496

    Article  PubMed  CAS  Google Scholar 

  • Song HK, Bochtler M, Azim MK, Hartmann C, Huber R, Ramachandran R (2003) Isolation and characterization of the prokaryotic proteasome homolog HslVU (ClpQY) from Thermotoga maritima and the crystal structure of HslV. Biophys Chem 100:437–452

    Article  PubMed  CAS  Google Scholar 

  • Studholme DJ, Rawlings ND, Barrett AJ, Bateman A (2003) A comparison of Pfam and MEROPS: two databases, one comprehensive, and one specialised. BMC Bioinformatics 4:17

    Article  PubMed  Google Scholar 

  • Stuhrmann M, Macek M Jr, Reis A, Schmidtke J, Tummler B, Dork T, Vavrova V, Macek M, Krawczak M (1990) Genotype analysis of cystic fibrosis patients in relation to pancreatic sufficiency. Lancet 335:738–739

    Article  PubMed  CAS  Google Scholar 

  • Stutts MJ, Rossier BC, Boucher RC (1997) Cystic fibrosis transmembrane conductance regulator inverts protein kinase A-mediated regulation of epithelial sodium channel single channel kinetics. J Biol Chem 272:14037–14040

    Article  PubMed  CAS  Google Scholar 

  • Sun Y, Zhang JN, Zhao D, Wang QS, Gu YC, Ma HP, Zhang ZR (2011) Role of the epithelial sodium channel in salt-sensitive hypertension. Acta Pharmacol Sin 32:789–797

    Article  PubMed  CAS  Google Scholar 

  • Suter S (1994) The role of bacterial proteases in the pathogenesis of cystic fibrosis. Am J Respir Crit Care Med 150:S118–S122

    PubMed  CAS  Google Scholar 

  • Talanian RV, Quinlan C, Trautz S, Hackett MC, Mankovich JA, Banach D, Ghayur T, Brady KD, Wong WW (1997) Substrate specificities of caspase family proteases. J Biol Chem 272:9677–9682

    Article  PubMed  CAS  Google Scholar 

  • Tan CD, Selvanathar IA, Baines DL (2011) Cleavage of endogenous gammaENaC and elevated abundance of alphaENaC are associated with increased Na transport in response to apical fluid volume expansion in human H441 airway epithelial cells. Pflugers Arch 462:431–441

    Article  PubMed  CAS  Google Scholar 

  • Tarran R, Trout L, Donaldson SH, Boucher RC (2006) Soluble mediators, not cilia, determine airway surface liquid volume in normal and cystic fibrosis superficial airway epithelia. J Gen Physiol 127:591–604

    Article  PubMed  CAS  Google Scholar 

  • Terheggen-Lagro SW, Rijkers GT, Ent CK van der (2005) The role of airway epithelium and blood neutrophils in the inflammatory response in cystic fibrosis. J Cyst Fibros 4 (Suppl 2):15–23

    Article  PubMed  CAS  Google Scholar 

  • Toder DS, Ferrell SJ, Nezezon JL, Rust L, Iglewski BH (1994) lasA and lasB genes of Pseudomonas aeruginosa: analysis of transcription and gene product activity. Infect Immun 62:1320–1327

    PubMed  CAS  Google Scholar 

  • Tomisugi Y, Unno M, Mizushima T, Morimoto Y, Tanahashi N, Tanaka K, Tsukihara T, Yasuoka N (2000) New crystal forms and low resolution structure analysis of 20 S proteasomes from bovine liver. J Biochem 127:941–943

    Article  PubMed  CAS  Google Scholar 

  • Tomlin KL, Coll OP, Ceri H (2001) Interspecies biofilms of Pseudomonas aeruginosa and Burkholderia cepacia. Can J Microbiol 47:949–954

    PubMed  CAS  Google Scholar 

  • Tong Z, Illek B, Bhagwandin VJ, Verghese GM, Caughey GH (2004) Prostasin, a membrane-anchored serine peptidase, regulates sodium currents in JME/CF15 cells, a cystic fibrosis airway epithelial cell line. Am J Physiol Lung Cell Mol Physiol 287:L928–L935

    Article  PubMed  CAS  Google Scholar 

  • Unno M, Mizushima T, Morimoto Y, Tomisugi Y, Tanaka K, Yasuoka N, Tsukihara T (2002) The structure of the mammalian 20 S proteasome at 2.75 Å resolution. Structure 10:609–618

    Article  PubMed  CAS  Google Scholar 

  • Uss RH, Fenton JW 2nd, Muraschi TF, Miller KD (1969) Two distinct elastases from different strains of Pseudomonas aeruginosa. Biochim Biophys Acta 191:179–181

    Article  PubMed  CAS  Google Scholar 

  • Vallet V, Chraibi A, Gaeggeler HP, Horisberger JD, Rossier BC (1997) An epithelial serine protease activates the amiloride-sensitive sodium channel. Nature 389:607–610

    Article  PubMed  CAS  Google Scholar 

  • Voynow JA, Fischer BM, Zheng S (2008) Proteases and cystic fibrosis. Int J Biochem Cell Biol 40:1238–1245

    Article  PubMed  CAS  Google Scholar 

  • Vuagniaux G, Vallet V, Jaeger NF, Pfister C, Bens M, Farman N, Courtois-Coutry N, Vandewalle A, Rossier BC, Hummler E (2000) Activation of the amiloride-sensitive epithelial sodium channel by the serine protease mCAP1 expressed in a mouse cortical collecting duct cell line. J Am Soc Nephrol 11:828–834

    PubMed  CAS  Google Scholar 

  • Vuagniaux G, Vallet V, Jaeger NF, Hummler E, Rossier BC (2002) Synergistic activation of ENaC by three membrane-bound channel-activating serine proteases (mCAP1, mCAP2, and mCAP3) and serum- and glucocorticoid-regulated kinase (Sgk1) in Xenopus oocytes. J Gen Physiol 120:191–201

    Article  PubMed  CAS  Google Scholar 

  • Wagner CA, Loffing-Cueni D, Yan Q, Schulz N, Fakitsas P, Carrel M, Wang T, Verrey F, Geibel JP, Giebisch G, Hebert SC, Loffing J (2008) Mouse model of type II Bartter’s syndrome. II. Altered expression of renal sodium- and water-transporting proteins. Am J Physiol Ren Physiol 294:F1373–F1380

    Article  CAS  Google Scholar 

  • Wiener-Kronish JP, Sakuma T, Kudoh I, Pittet JF, Frank D, Dobbs L, Vasil ML, Matthay MA (1993) Alveolar epithelial injury and pleural empyema in acute P. aeruginosa pneumonia in anesthetized rabbits. J Appl Physiol 75:1661–1669

    PubMed  CAS  Google Scholar 

  • Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214:199–210

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Conway JF, Thibodeau PH (2012) Calcium-induced folding and stabilization of the Pseudomonas aeruginosa alkaline protease. J Biol Chem 287:4311–4322

    Article  PubMed  CAS  Google Scholar 

  • Zhou Z, Duerr J, Johannesson B, Schubert SC, Treis D, Harm M, Graeber SY, Dalpke A, Schultz C, Mall MA (2011) The ENaC-overexpressing mouse as a model of cystic fibrosis lung disease. J Cyst Fibros 10 (Suppl 2):S172–S182

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Cell Biology, University of Pittsburgh School of Medicine, 3500 Terrace Street, S327 Biomedical Science Tower, Pittsburgh, PA 15261, USA

    P. H. Thibodeau

  2. Department of Cell Biology, University of Pittsburgh School of Medicine, 3500 Terrace Street, S314 Biomedical Science Tower, Pittsburgh, PA 15261, USA

    M. B. Butterworth

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Correspondence to M. B. Butterworth.

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This work was supported by NIH grants to M.B. (K99DK078917, P30DK079307) and P.T. (R01DK083284).

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Thibodeau, P.H., Butterworth, M.B. Proteases, cystic fibrosis and the epithelial sodium channel (ENaC). Cell Tissue Res 351, 309–323 (2013). https://doi.org/10.1007/s00441-012-1439-z

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