A new C-terminal cleavage product of procaspase-8, p30, defines an alternative pathway of procaspase-8 activation.
Caspase-8 is the main initiator caspase in death receptor-induced apoptosis. Procaspase-8 is activated at the death-inducing signaling complex (DISC). Previous studies suggested a two-step model of procaspase-8 activation. The first cleavage step occurs between the protease domains p18 and p10. The second cleavage step takes place between the prodomain and the large protease subunit (p18). Subsequently, the active caspase-8 heterotetramer p18(2)-p10(2) is released into the cytosol, starting the apoptotic signaling cascade. In this report, we have further analyzed procaspase-8 processing upon death receptor stimulation directly at the DISC and in the cytosol. We have found an alternative sequence of cleavage events for procaspase-8. We have demonstrated that the first cleavage can also occur between the prodomain and the large protease subunit (p18). The resulting cleavage product, p30, contains both the large protease subunit (p18) and the small protease subunit (p10). p30 is further processed to p10 and p18 by active caspases. Furthermore, we show that p30 can sensitize cells toward death receptor-induced apoptosis. Taken together, our data suggest an alternative mechanism of procaspase-8 activation at the DISC.
Hoffmann
Julia C
JC
Division of Immunogenetics, Tumorimmunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D69120 Heidelberg, Germany.
Pappa
Alexander
A
Krammer
Peter H
PH
Lavrik
Inna N
IN
D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D053218:Receptors, Death Domain / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D010446:Peptide Fragments; D053218:Receptors, Death Domain; D019014:fas Receptor; D053181:Caspase 8; D020169:Caspases