title: Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis.
abstract: Pancreatitis is associated with premature activation of digestive proteases in the pancreas. The lysosomal hydrolase cathepsin B (CTSB) is a known activator of trypsinogen, and its deletion reduces disease severity in experimental pancreatitis. Here we studied the activation mechanism and subcellular compartment in which CTSB regulates protease activation and cellular injury. Cholecystokinin (CCK) increased the activity of CTSB, cathepsin L, trypsin, chymotrypsin, and caspase 3 in vivo and in vitro and induced redistribution of CTSB to a secretory vesicle-enriched fraction. Neither CTSB protein nor activity redistributed to the cytosol, where the CTSB inhibitors cystatin-B/C were abundantly present. Deletion of CTSB reduced and deletion of cathepsin L increased intracellular trypsin activation. CTSB deletion also abolished CCK-induced caspase 3 activation, apoptosis-inducing factor, as well as X-linked inhibitor of apoptosis protein degradation, but these depended on trypsinogen activation via CTSB. Raising the vesicular pH, but not trypsin inhibition, reduced CTSB activity. Trypsin inhibition did not affect apoptosis in hepatocytes. Deletion of CTSB affected apoptotic but not necrotic acinar cell death. In summary, CTSB in pancreatitis undergoes activation in a secretory, vesicular, and acidic compartment where it activates trypsinogen. Its deletion or inhibition regulates acinar cell apoptosis but not necrosis in two models of pancreatitis. Caspase 3-mediated apoptosis depends on intravesicular trypsinogen activation induced by CTSB, not CTSB activity directly, and this mechanism is pancreas-specific.
authors.affiliation: From the Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Sendler
authors.affiliation: From the Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany.
authors.forename: Sandrina
authors.initials: S
authors.lastname: Maertin
authors.affiliation: From the Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: John
authors.affiliation: From the Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Persike
authors.affiliation: From the Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany.
authors.forename: F Ulrich
authors.initials: FU
authors.lastname: Weiss
authors.affiliation: the Division of Medical Biology, University of Rostock, 18057 Rostock, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Krüger
authors.affiliation: the Division of Experimental Surgery, Department of Surgery, Otto von Guericke University, 39120 Magdeburg, Germany, and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wartmann
authors.affiliation: From the Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany.
authors.forename: Preshit
authors.initials: P
authors.lastname: Wagh
authors.affiliation: the Division of Experimental Surgery, Department of Surgery, Otto von Guericke University, 39120 Magdeburg, Germany, and.
authors.forename: Walter
authors.initials: W
authors.lastname: Halangk
authors.affiliation: the Fakultät für Chemie, Hochschule Aalen, 73430 Aalen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Schaschke
authors.affiliation: From the Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.affiliation: From the Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany, lerch@uni-greifswald.de.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
mesh_terms: D000818:Animals; D017209:Apoptosis; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000201:enzymology*; D010195:Pancreatitis / Q000201:enzymology / Q000473:pathology*; D010447:Peptide Hydrolases / Q000378:metabolism*; D013347:Subcellular Fractions / Q000201:enzymology
chemical_list: D010447:Peptide Hydrolases; D002401:Cathepsin B
keywords: apoptosis; autophagy; cathepsin B (CTSB); cell death; chymotrypsin; pancreas; pancreatitis; trypsin activation