title: Caspase 8-mediated cleavage of plectin precedes F-actin breakdown in acinar cells during pancreatitis.
abstract: Pancreatic acinar cells depend on the integrity of the cytoskeleton for regulated secretion. Stimulation of isolated rat pancreatic acini with the secretagogue CCK serves as a model for human acute edematous pancreatitis. It induces the breakdown of the actin filament system (F-actin) with the consecutive inhibition of secretion and premature activation of digestive enzymes. However, the mechanisms that regulate F-actin breakdown are largely unknown. Plectin is a versatile cytolinker protein regulating F-actin dynamics in fibroblasts. It was recently demonstrated that plectin is a substrate of caspase 8. In pancreatic acinar cells, plectin strongly colocalizes with apical and basolateral F-actin. Supramaximal secretory stimulation of acini with CCK leads to a rapid redistribution and activation of caspase 8, followed by degradation of plectin that in turn precedes the F-actin breakdown. Inhibition of caspase 8 before CCK hyperstimulation prevents plectin cleavage, stabilizes F-actin morphology, and reverses the inhibition of secretion. Thus we propose that the caspase 8-mediated degradation of plectin represents a critical biochemical event during CCK-induced secretory blockade and cell injury.
authors.affiliation: Department of Internal Medicine I, University of Ulm, 89070 Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Beil
authors.forename: Jürgen
authors.initials: J
authors.lastname: Leser
authors.forename: Manfred P
authors.initials: MP
authors.lastname: Lutz
authors.forename: Anna
authors.initials: A
authors.lastname: Gukovskaya
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
authors.forename: Grit
authors.initials: G
authors.lastname: Lynch
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
authors.forename: Guido
authors.initials: G
authors.lastname: Adler
mesh_terms: D000199:Actins / Q000378:metabolism*; D000681:Amylases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism* / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010195:Pancreatitis / Q000378:metabolism*; D051190:Plectin; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007381:Intermediate Filament Proteins; C495334:Plec protein, rat; D051190:Plectin; D011994:Recombinant Proteins; D002766:Cholecystokinin; D000681:Amylases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases