Inhibition of cellular processing of surfactant protein C by drugs affecting intracellular pH gradients.
Identifieur interne : 002971 ( Main/Exploration ); précédent : 002970; suivant : 002972Inhibition of cellular processing of surfactant protein C by drugs affecting intracellular pH gradients.
Auteurs : M F Beers [États-Unis]Source :
- The Journal of biological chemistry [ 0021-9258 ] ; 1996.
Descripteurs français
- KwdFr :
- Animaux, Antibactériens (pharmacologie), Anticorps, Antienzymes (pharmacologie), Cellules cultivées, Chloroquine (pharmacologie), Cinétique, Concentration en ions d'hydrogène, Facteurs temps, Fractions subcellulaires (), Fractions subcellulaires (métabolisme), Ionophores (pharmacologie), Macrolides, Maturation post-traductionnelle des protéines (), Modèles biologiques, Monensin (pharmacologie), Méthylamines (pharmacologie), Poumon (cytologie), Poumon (métabolisme), Protéolipides (biosynthèse), Protéolipides (isolement et purification), Précurseurs de protéines (isolement et purification), Précurseurs de protéines (métabolisme), Radio-isotopes du soufre, Rat Sprague-Dawley, Rats, Surfactants pulmonaires (biosynthèse), Surfactants pulmonaires (isolement et purification), Vacuoles (), Vacuoles (métabolisme), Épitopes.
- MESH :
- biosynthèse : Protéolipides, Surfactants pulmonaires.
- cytologie : Poumon.
- isolement et purification : Protéolipides, Précurseurs de protéines, Surfactants pulmonaires.
- métabolisme : Fractions subcellulaires, Poumon, Précurseurs de protéines, Vacuoles.
- pharmacologie : Antibactériens, Antienzymes, Chloroquine, Ionophores, Monensin, Méthylamines.
- Animaux, Anticorps, Cellules cultivées, Cinétique, Concentration en ions d'hydrogène, Facteurs temps, Fractions subcellulaires, Macrolides, Maturation post-traductionnelle des protéines, Modèles biologiques, Radio-isotopes du soufre, Rat Sprague-Dawley, Rats, Vacuoles, Épitopes.
English descriptors
- KwdEn :
- Animals, Anti-Bacterial Agents (pharmacology), Antibodies, Cells, Cultured, Chloroquine (pharmacology), Enzyme Inhibitors (pharmacology), Epitopes, Hydrogen-Ion Concentration, Ionophores (pharmacology), Kinetics, Lung (cytology), Lung (metabolism), Macrolides, Methylamines (pharmacology), Models, Biological, Monensin (pharmacology), Protein Precursors (isolation & purification), Protein Precursors (metabolism), Protein Processing, Post-Translational (drug effects), Proteolipids (biosynthesis), Proteolipids (isolation & purification), Pulmonary Surfactants (biosynthesis), Pulmonary Surfactants (isolation & purification), Rats, Rats, Sprague-Dawley, Subcellular Fractions (drug effects), Subcellular Fractions (metabolism), Sulfur Radioisotopes, Time Factors, Vacuoles (drug effects), Vacuoles (metabolism).
- MESH :
- chemical , biosynthesis : Proteolipids, Pulmonary Surfactants.
- chemical , isolation & purification : Protein Precursors, Proteolipids, Pulmonary Surfactants.
- chemical , metabolism : Protein Precursors.
- chemical , pharmacology : Anti-Bacterial Agents, Chloroquine, Enzyme Inhibitors, Ionophores, Methylamines, Monensin.
- cytology : Lung.
- drug effects : Protein Processing, Post-Translational, Subcellular Fractions, Vacuoles.
- metabolism : Lung, Subcellular Fractions, Vacuoles.
- Animals, Antibodies, Cells, Cultured, Epitopes, Hydrogen-Ion Concentration, Kinetics, Macrolides, Models, Biological, Rats, Rats, Sprague-Dawley, Sulfur Radioisotopes, Time Factors.
Abstract
Surfactant protein C (SP-C) is a hydrophobic protein synthesized and secreted exclusively by alveolar type II cells through proteolysis of a 21-kDa propeptide (SP-C21) to produce the 3.7-kDa surface active form. Previous studies from this laboratory have demonstrated that early processing of proSP-C involves extensive intracellular proteolysis of the COOH terminus of proSP-C21 in subcellular compartments, which include the acidic type II cell-specific subcellular organelle, the lamellar body. (Beers, M. F., Kim, C. Y., Dodia, C., and Fisher, A. B.(1994) J. Biol. Chem. 269, 20318-20328). The role of intracellular pH gradients in SP-C processing was studied in freshly isolated rat type II cells. Using vital fluorescence microscopy, the pH indicator acridine orange (AO) identified intense fluorescence staining of acidic cytoplasmic vesicles within fresh type II cells. The AO vesicular staining pattern was similar in cells labeled with the lamellar body marker phosphine 3R and the phospholipid dye nile red. AO fluorescence was quenched by the addition of a membrane-permeable weak base, methylamine. Immunoprecipitation of cell lysates with anti-proSP-C antisera following pulse-chase labeling (0-2 h) with 35S-Translabel demonstrated rapid synthesis of 35S-proSP-C21 with a time-dependent appearance of 16- and 6-kDa intermediates (SP-C16 and SP-C6). Tricine polyacrylamide gel electrophoresis analysis of organic extracts of cell lysates showed time-dependent appearance of mature SP-C3.7. The addition of 5 mM methylamine significantly blocked the post-translational processing of proSP-C resulting in disruption of normal precursor-product relationships and inhibition of SP-C3.7 formation. Methylamine-treated cells exhibited slow accumulation of SP-C16 and SP-C6, a persistence of SP-C21, and an absence of SP-C3.7 for the duration of the chase period. The lysosomotropic agent chloroquine, the proton ionophore monensin, and bafilomycin A1, a specific vacuolar H+-ATPase inhibitor, each caused inhibition of proSP-C processing in a similar manner. These results demonstrate that normal post-translational proteolysis of proSP-C occurs in acidic intracellular compartments, which include the lamellar body, and that complete processing to SP-C3.7 is dependent upon maintenance of transmembrane pH gradients by a vacuolar H+-ATPase.
DOI: 10.1074/jbc.271.24.14361
PubMed: 8662952
Affiliations:
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Le document en format XML
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Anti-Bacterial Agents (pharmacology)</term>
<term>Antibodies</term>
<term>Cells, Cultured</term>
<term>Chloroquine (pharmacology)</term>
<term>Enzyme Inhibitors (pharmacology)</term>
<term>Epitopes</term>
<term>Hydrogen-Ion Concentration</term>
<term>Ionophores (pharmacology)</term>
<term>Kinetics</term>
<term>Lung (cytology)</term>
<term>Lung (metabolism)</term>
<term>Macrolides</term>
<term>Methylamines (pharmacology)</term>
<term>Models, Biological</term>
<term>Monensin (pharmacology)</term>
<term>Protein Precursors (isolation & purification)</term>
<term>Protein Precursors (metabolism)</term>
<term>Protein Processing, Post-Translational (drug effects)</term>
<term>Proteolipids (biosynthesis)</term>
<term>Proteolipids (isolation & purification)</term>
<term>Pulmonary Surfactants (biosynthesis)</term>
<term>Pulmonary Surfactants (isolation & purification)</term>
<term>Rats</term>
<term>Rats, Sprague-Dawley</term>
<term>Subcellular Fractions (drug effects)</term>
<term>Subcellular Fractions (metabolism)</term>
<term>Sulfur Radioisotopes</term>
<term>Time Factors</term>
<term>Vacuoles (drug effects)</term>
<term>Vacuoles (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Antibactériens (pharmacologie)</term>
<term>Anticorps</term>
<term>Antienzymes (pharmacologie)</term>
<term>Cellules cultivées</term>
<term>Chloroquine (pharmacologie)</term>
<term>Cinétique</term>
<term>Concentration en ions d'hydrogène</term>
<term>Facteurs temps</term>
<term>Fractions subcellulaires ()</term>
<term>Fractions subcellulaires (métabolisme)</term>
<term>Ionophores (pharmacologie)</term>
<term>Macrolides</term>
<term>Maturation post-traductionnelle des protéines ()</term>
<term>Modèles biologiques</term>
<term>Monensin (pharmacologie)</term>
<term>Méthylamines (pharmacologie)</term>
<term>Poumon (cytologie)</term>
<term>Poumon (métabolisme)</term>
<term>Protéolipides (biosynthèse)</term>
<term>Protéolipides (isolement et purification)</term>
<term>Précurseurs de protéines (isolement et purification)</term>
<term>Précurseurs de protéines (métabolisme)</term>
<term>Radio-isotopes du soufre</term>
<term>Rat Sprague-Dawley</term>
<term>Rats</term>
<term>Surfactants pulmonaires (biosynthèse)</term>
<term>Surfactants pulmonaires (isolement et purification)</term>
<term>Vacuoles ()</term>
<term>Vacuoles (métabolisme)</term>
<term>Épitopes</term>
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<keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Proteolipids</term>
<term>Pulmonary Surfactants</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="isolation & purification" xml:lang="en"><term>Protein Precursors</term>
<term>Proteolipids</term>
<term>Pulmonary Surfactants</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Protein Precursors</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-Bacterial Agents</term>
<term>Chloroquine</term>
<term>Enzyme Inhibitors</term>
<term>Ionophores</term>
<term>Methylamines</term>
<term>Monensin</term>
</keywords>
<keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Protéolipides</term>
<term>Surfactants pulmonaires</term>
</keywords>
<keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Poumon</term>
</keywords>
<keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Lung</term>
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<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Protein Processing, Post-Translational</term>
<term>Subcellular Fractions</term>
<term>Vacuoles</term>
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<keywords scheme="MESH" qualifier="isolement et purification" xml:lang="fr"><term>Protéolipides</term>
<term>Précurseurs de protéines</term>
<term>Surfactants pulmonaires</term>
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<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lung</term>
<term>Subcellular Fractions</term>
<term>Vacuoles</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Fractions subcellulaires</term>
<term>Poumon</term>
<term>Précurseurs de protéines</term>
<term>Vacuoles</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antibactériens</term>
<term>Antienzymes</term>
<term>Chloroquine</term>
<term>Ionophores</term>
<term>Monensin</term>
<term>Méthylamines</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Antibodies</term>
<term>Cells, Cultured</term>
<term>Epitopes</term>
<term>Hydrogen-Ion Concentration</term>
<term>Kinetics</term>
<term>Macrolides</term>
<term>Models, Biological</term>
<term>Rats</term>
<term>Rats, Sprague-Dawley</term>
<term>Sulfur Radioisotopes</term>
<term>Time Factors</term>
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<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Anticorps</term>
<term>Cellules cultivées</term>
<term>Cinétique</term>
<term>Concentration en ions d'hydrogène</term>
<term>Facteurs temps</term>
<term>Fractions subcellulaires</term>
<term>Macrolides</term>
<term>Maturation post-traductionnelle des protéines</term>
<term>Modèles biologiques</term>
<term>Radio-isotopes du soufre</term>
<term>Rat Sprague-Dawley</term>
<term>Rats</term>
<term>Vacuoles</term>
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<front><div type="abstract" xml:lang="en">Surfactant protein C (SP-C) is a hydrophobic protein synthesized and secreted exclusively by alveolar type II cells through proteolysis of a 21-kDa propeptide (SP-C21) to produce the 3.7-kDa surface active form. Previous studies from this laboratory have demonstrated that early processing of proSP-C involves extensive intracellular proteolysis of the COOH terminus of proSP-C21 in subcellular compartments, which include the acidic type II cell-specific subcellular organelle, the lamellar body. (Beers, M. F., Kim, C. Y., Dodia, C., and Fisher, A. B.(1994) J. Biol. Chem. 269, 20318-20328). The role of intracellular pH gradients in SP-C processing was studied in freshly isolated rat type II cells. Using vital fluorescence microscopy, the pH indicator acridine orange (AO) identified intense fluorescence staining of acidic cytoplasmic vesicles within fresh type II cells. The AO vesicular staining pattern was similar in cells labeled with the lamellar body marker phosphine 3R and the phospholipid dye nile red. AO fluorescence was quenched by the addition of a membrane-permeable weak base, methylamine. Immunoprecipitation of cell lysates with anti-proSP-C antisera following pulse-chase labeling (0-2 h) with 35S-Translabel demonstrated rapid synthesis of 35S-proSP-C21 with a time-dependent appearance of 16- and 6-kDa intermediates (SP-C16 and SP-C6). Tricine polyacrylamide gel electrophoresis analysis of organic extracts of cell lysates showed time-dependent appearance of mature SP-C3.7. The addition of 5 mM methylamine significantly blocked the post-translational processing of proSP-C resulting in disruption of normal precursor-product relationships and inhibition of SP-C3.7 formation. Methylamine-treated cells exhibited slow accumulation of SP-C16 and SP-C6, a persistence of SP-C21, and an absence of SP-C3.7 for the duration of the chase period. The lysosomotropic agent chloroquine, the proton ionophore monensin, and bafilomycin A1, a specific vacuolar H+-ATPase inhibitor, each caused inhibition of proSP-C processing in a similar manner. These results demonstrate that normal post-translational proteolysis of proSP-C occurs in acidic intracellular compartments, which include the lamellar body, and that complete processing to SP-C3.7 is dependent upon maintenance of transmembrane pH gradients by a vacuolar H+-ATPase.</div>
</front>
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