Caspase-8 can be activated by interchain proteolysis without receptor-triggered dimerization during drug-induced apoptosis.
Proteases of the caspase family are thought to be activated by proteolytic processing of their inactive zymogens. However, although proteolytic cleavage is sufficient for executioner caspases, a different mechanism has been recently proposed for initiator caspases, such as caspase-8, which are believed to be activated by proximity-induced dimerization. According to this model, dimerization rather than proteolytic processing is considered as the critical event for caspase-8 activation. Such a mechanism would suggest that in the absence of a dimerization platform such as the death-inducing signaling complex, caspase-8 proteolytic cleavage would result in an inactive enzyme. As several studies have described caspase-8 cleavage during mitochondrial apoptosis, we now investigated whether caspase-8 becomes indeed catalytically active in this pathway. Using an in vivo affinity labeling approach, we demonstrate that caspase-8 is activated in etoposide-treated cells in vivo in the absence of the receptor-induced death-inducing signaling complex formation. Furthermore, we show that both caspase-3 and -6 are required for the efficient activation of caspase-8. Our data therefore indicate that interchain cleavage of caspase-8 in the mitochondrial pathway is sufficient to produce an active enzyme even in the absence of receptor-driven procaspase-8 dimerization.
Sohn
Dennis
D
Institute of Molecular Medicine, Heinrich-Heine-University, D-40225 Düsseldorf, Germany.
Schulze-Osthoff
Klaus
K
Jänicke
Reiner U
RU
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D020169:Caspases / Q000737:chemistry* / Q000378:metabolism*; D045744:Cell Line, Tumor; D019281:Dimerization; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism
D010446:Peptide Fragments; D019014:fas Receptor; D005047:Etoposide; D010447:Peptide Hydrolases; C505407:CASP3 protein, human; C505514:CASP6 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D020169:Caspases