TAILIEUCHUNG - Báo cáo khoa học: Endosomal proteolysis of diphtheria toxin without toxin translocation into the cytosol of rat liver in vivo

A detailed proteolysis study of internalized diphtheria toxin (DT) within rat liver endosomes was undertaken to determine whether DT-resistant species exhibit defects in toxin endocytosis, toxin activation by cellular enzymes or toxin translocation to its cytosolic target. | ễFEBS Journal Endosomal proteolysis of diphtheria toxin without toxin translocation into the cytosol of rat liver in vivo Tatiana El Hage1 2 Paulette Decottignies3 4 and Francois Authier1 2 1 INSERM U756 Chatenay-Malabry France 2 Universite Paris-Sud Faculte de Pharmacie Chatenay-Malabry France 3 CNRS UMR 8619 Orsay France 4 University Paris-Sud Orsay France Keywords cathepsin D diphtheria toxin endosome furin translocation Correspondence F. Authier Inserm U756 Universite Paris-Sud Faculte de Pharmacie 5 rue JeanBaptiste Clement 92296 Chatenay-Malabry France Fax 33 1 4683 5844 Tel 33 1 4683 5528 E-mail Received 4 July 2007 revised 19 January 2008 accepted 8 February 2008 doi A detailed proteolysis study of internalized diphtheria toxin DT within rat liver endosomes was undertaken to determine whether DT-resistant species exhibit defects in toxin endocytosis toxin activation by cellular enzymes or toxin translocation to its cytosolic target. Following administration of a saturating dose of wild-type DT or nontoxic mutant DT mDT to rats rapid endocytosis of the intact 62-kDa toxin was observed coincident with the endosomal association of DT-A low association and DT-B high association subunits. Assessment of the subsequent post-endosomal fate of internalized mDT revealed a sustained endo-lysosomal transfer of the mDT-B subunit accompanied by a net decrease in intact mDT and mDT-A subunit throughout the endo-lysosomal apparatus. In vitro proteolysis of DT using an endosomal lysate was observed at both neutral and acidic pH with the subsequent generation of DT-A and DT-B subunits pH 7 or DT fragments with low ADP-ribosyltransferase activity pH 4 . Biochemical characterization revealed that the neutral endosomal DT-degrading activity was due to a novel luminal 70-kDa furin enzyme whereas the aspartic acid protease cathepsin D EC was identified as being responsible for toxin degradation at acidic pH. .

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