TAILIEUCHUNG - Báo cáo khoa học: Proteolytic activation of internalized cholera toxin within hepatic endosomes by cathepsin D

We have defined thein vivo andin vitro metabolic fate of internalized chol-era toxin (CT) in the endosomal apparatus of rat liver. In vivo, CT was internalized and accumulated in endosomes where it underwent degrada-tion in a pH-dependent manner. In vitro proteolysis of CT using an endo-somal lysate required an acidic pH and was sensitive to pepstatin A, an inhibitor of aspartic acid proteases. | ềFEBS Journal Proteolytic activation of internalized cholera toxin within hepatic endosomes by cathepsin D Clemence Merlen Domitille Fayol-Messaoudi Sylvie Fabrega Tatiana El Hage Alain Servin and Francois Authier Institut Nationalde la Sante et de la Recherche Medicale U510 Faculte de Pharmacie Paris XI Chatenay-Malabry France Keywords cathepsin D cholera toxin endocytosis hepatocyte proteolysis Correspondence F. Authier INSERM U510 Faculte de Pharmacie Paris XI 5 rue Jean-Baptiste Clement 92296 Chatenay-Malabry France Fax 33 1 46835844 Tel 33 1 46835843 E-mail These authors contributed equally to the paper Received 29 April2005 revised 1 July 2005 accepted 7 July 2005 doi We have defined the in vivo and in vitro metabolic fate of internalized cholera toxin CT in the endosomal apparatus of rat liver. In vivo CT was internalized and accumulated in endosomes where it underwent degradation in a pH-dependent manner. In vitro proteolysis of CT using an endo-somal lysate required an acidic pH and was sensitive to pepstatin A an inhibitor of aspartic acid proteases. By nondenaturating immunoprecipitation the acidic CT-degrading activity was attributed to the luminal form of endosomal cathepsin D. The rate of toxin hydrolysis using an endosomal lysate or pure cathepsin D was found to be high for native CT and free CT-B subunit and low for free CT-A subunit. On the basis of IC50 values competition studies revealed that CT-A and CT-B subunits share a common binding site on the cathepsin D enzyme with native CT and free CT-B subunit displaying the highest affinity for the protease. By immunofluorescence partial colocalization of internalized CT with cathepsin D was confirmed at early times of endocytosis in both hepatoma HepG2 and intestinal Caco-2 cells. Hydrolysates of CT generated at low pH by bovine cathepsin D displayed ADP-ribosyltransferase activity towards exogenous Gsa protein suggesting that CT .

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