TAILIEUCHUNG - Báo cáo khoa học: Proteolysis of Pseudomonas exotoxin A within hepatic endosomes by cathepsins B and D produces fragments displaying in vitro ADP-ribosylating and apoptotic effects

To assessPseudomonasexotoxin A (ETA) compartmentalization, process-ing and cytotoxicity in vivo, we have studied the fate of internalized ETA with the use of thein vivo rodent liver model following toxin administra-tion, cell-free hepatic endosomes, and pure in vitro protease assays. ETA taken up into rat liver in vivo was rapidly associated with plasma mem-branes (5–30 min), internalized within endosomes (15–60 min), and later translocated into the cytosolic compartment (30–90 min). | ỊFEBS Journal Proteolysis of Pseudomonas exotoxin A within hepatic endosomes by cathepsins B and D produces fragments displaying in vitro ADP-ribosylating and apoptotic effects Tatiana El Hage1 2 Severine Lorin3 Paulette Decottignies4 5 Mojgan Djavaheri-Mergny6 and Francois Authier1 2 1 INSERM Chatenay-Malabry France 2 Universite Paris-Sud Faculte de Pharmacie Chatenay-Malabry France 3 JE 2493 Universite Paris-Sud Faculte de Pharmacie Chatenay-Malabry France 4 CNRS UMR 8619 Orsay France 5 Universite Paris-Sud Orsay France 6 INSERM VINCO U916 Institut Bergonie Bordeaux France Keywords cathepsin endocytosis endosome Pseudomonas exotoxin A translocation Correspondence F. Authier INSERM Universite Paris-Sud Faculte de Pharmacie 5 rue Jean-Baptiste Clement 92296 Chatenay-Malabry France Fax 33 1 46835844 Tel 33 1 46835291 E-mail Received 21 March 2010 revised 4 June 2010 accepted 12 July 2010 doi To assess Pseudomonas exotoxin A ETA compartmentalization processing and cytotoxicity in vivo we have studied the fate of internalized ETA with the use of the in vivo rodent liver model following toxin administration cell-free hepatic endosomes and pure in vitro protease assays. ETA taken up into rat liver in vivo was rapidly associated with plasma membranes 5-30 min internalized within endosomes 15-60 min and later translocated into the cytosolic compartment 30-90 min . Coincident with endocytosis of intact ETA in vivo association of the catalytic ETA-A subunit and low molecular mass ETA-A fragments was observed in the endosomal apparatus. After an in vitro proteolytic assay with an endoso-mal lysate and pure proteases the ETA-degrading activity was attributed to the luminal species of endosomal acidic cathepsins B and D with the major cleavages generated in vitro occurring mainly within domain III of ETA-A. Cell-free endosomes preloaded in vivo with ETA intraluminally processed and extraluminally released intact ETA .

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