Switch in Fas-activated death signaling pathway as result of keratin 8/18-intermediate filament loss.
Fas-induced apoptosis is initiated through the recruitment of FADD and procaspase 8 to form the death-inducing signaling complex (DISC). In some cells (type I cells) the initiator caspase 8 directly activates effector caspases such as procaspase 3, whereas in others (type II cells) the death signal is amplified through mitochondria. In epithelial cells, Fas-induced hierarchic caspase activation is also linked with DEDD, a member of the DED family that binds to keratin (K) intermediate filaments (IFs). Hepatocytes are type II cells and their IFs are made exclusively of K8/K18. We have shown previously that K8-null mouse hepatocytes, lacking K8/K18 IFs, are more sensitive than their wild-type counterparts to Fas-induced apoptosis. Here, by examining the cell-death kinetics and death-signaling ordering, we found that K8-null hepatocytes exhibited prominent DISC formation, higher procaspase 8 activation and direct procaspase 3 activation as reported for type I cells; however they experienced a reduced Bid cleavage and a stronger procaspase 9 activation. In addition, the K8/K18 loss altered the DEDD ubiquitination status and nuclear/cytoplasmic distribution. Together, the results suggest that the K8/K18 loss induces a switch in Fas-induced death signaling, likely through a DEDD involvement.
Gilbert
Stéphane
S
Département de Médecine, Centre de Recherche en Cancérologie, Université Laval, Quebec City, QC, Canada.
Ruel
Alexandre
A
Loranger
Anne
A
Marceau
Normand
N
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D007382:Intermediate Filaments / Q000378:metabolism*; D053538:Keratin-18 / Q000235:genetics / Q000378:metabolism*; D053533:Keratin-8 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D000906:Antibodies; D051023:BH3 Interacting Domain Death Agonist Protein; D053418:Death Domain Receptor Signaling Adaptor Proteins; C486432:Dedd protein, mouse; D053538:Keratin-18; D053533:Keratin-8; D019014:fas Receptor; D045304:Cytochromes c; D020169:Caspases