title: Specific cleavage of the lung surfactant protein A by human cathepsin S may impair its antibacterial properties.
abstract: Human cysteine cathepsins (Cats) are implicated in lung injuries and tissue remodeling and have recently emerged as important players in pulmonary inflammations. The proteolytic activities of Cat B, L, K, S and H are dramatically increased in the sputum of patients with cystic fibrosis (CF), suggesting a possible involvement in the CF pathophysiology. We found that pulmonary surfactant protein A (SP-A) that participates to innate host defense is extensively degraded in CF expectorations. Breakdown of SP-A was markedly decreased in CF sputum by E-64 and Mu-Leu-Hph-VSPh, a Cat S inhibitor. Cat S cleaved efficiently and specifically SP-A within critical residues of the solvent-exposed loop of its carbohydrate recognition (C-type lectin) domain that allows binding to pathogens. Cat S decreased aggregation properties of SP-A (self-aggregation, aggregation of phospholipid vesicles and rough LPS). Moreover cleavage of SP-A by Cat S reduced binding to yeast mannan and impaired agglutination of Escherichia coli and Pseudomonas aeruginosa, a foremost detrimental pathogen colonizing the lungs of CF patients. Besides human neutrophil serine proteases and bacterial proteases, we propose that Cat S may participate in the pathophysiology of CF by weakening the antibacterial activity of SP-A. More broadly, present results provide further indication that Cat S, along with Cats B and L, could display immuno-modulatory functions by inactivating key proteins involved in the innate immunity defense.
authors.affiliation: Université François Rabelais, Tours, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lecaille
authors.forename: Clément
authors.initials: C
authors.lastname: Naudin
authors.forename: Juliette
authors.initials: J
authors.lastname: Sage
authors.forename: Alix
authors.initials: A
authors.lastname: Joulin-Giet
authors.forename: Agnès
authors.initials: A
authors.lastname: Courty
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Andrault
authors.forename: Ruud A W
authors.initials: RA
authors.lastname: Veldhuizen
authors.forename: Fred
authors.initials: F
authors.lastname: Possmayer
authors.forename: Gilles
authors.initials: G
authors.lastname: Lalmanach
mesh_terms: D000371:Agglutination; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism*; D002417:Cattle; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D011550:Pseudomonas aeruginosa / Q000378:metabolism; D037662:Pulmonary Surfactant-Associated Protein A / Q000737:chemistry / Q000378:metabolism*; D013183:Sputum / Q000201:enzymology; D013379:Substrate Specificity
chemical_list: D000900:Anti-Bacterial Agents; D037662:Pulmonary Surfactant-Associated Protein A; D002403:Cathepsins; C028217:cathepsin S; D002118:Calcium
keywords: 1,2-dipalmitoyl-sn-glycero-3-phosphocholine; 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol; 3-NO(2)-Tyr; 3-nitro-tyrosine; 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride; 7-amino-4-methyl coumarin; AEBSF; AMC; Abz; Antimicrobial protein; BALF; BCA; CA-074; CF; Cat; Collectin; Cysteine protease; Cystic fibrosis; DL-dithiothreitol; DPPC; DPPG; DTT; E-64; FRET; HNE; L-3-carboxy-trans-2.3-epoxypropionyl-leucylamido-(4-guanidino) butane; Lung; MMTs; Mu-Leu-Hph-VSPh; N-(l-3-trans-propylcarbamoyloxirane-2-carbonyl)-l-isoleucyl-l-proline; NSP; P. aeruginosa-negative; PMA; PMSF; Proteolysis; Ps+; Ps-; Pseudomonas aeruginosa-positive; RT; SP-A; TBS; Z; benzyloxycarbonyl; bicinchoninic acid; broncho-alveolar lavage fluid; cathepsin; cystic fibrosis; fluorescence resonance energy transfer; human neutrophil elastase; methylmethanethiosulfonate; morpholine urea-leucyl-homophenylalanyl-(vinylsulfonyl)benzene; neutrophil serine protease; ortho-aminobenzoic acid; phenylmethylsulfonyl fluoride; phorbol 12-myristate 13-acetate; room temperature; surfactant protein A; tris buffer saline