Caspase 8-mediated cleavage of plectin precedes F-actin breakdown in acinar cells during pancreatitis.
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.
Beil
Michael
M
Department of Internal Medicine I, University of Ulm, 89070 Ulm, Germany.
Leser
Jürgen
J
Lutz
Manfred P
MP
Gukovskaya
Anna
A
Seufferlein
Thomas
T
Lynch
Grit
G
Pandol
Stephen J
SJ
Adler
Guido
G
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
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