Interchain proteolysis, in the absence of a dimerization stimulus, can initiate apoptosis-associated caspase-8 activation.
Caspases coordinate the internal demolition of the cell that is seen during apoptosis. Proteolytic processing of caspases is observed during apoptosis, and this correlates with conversion of inactive caspase proenzymes into their active two-chain forms. However, recent studies have suggested that caspase-8 is activated through dimerization and that interchain proteolysis is not sufficient for activation of this caspase. This proposal casts doubt upon whether caspase-8 is productively activated by granzyme B during granule-dependent cytotoxic T lymphocyte or natural killer cell-mediated killing, for example. Contrary to the dimerization model, we show that direct proteolysis of caspase-8 by the cytotoxic T lymphocyte protease granzyme B, or by caspase-6, produces an active enzyme that displays robust proteolytic activity toward synthetic as well as natural caspase-8 substrates. These data suggest that enforced dimerization of caspase-8 zymogens by scaffold proteins such as Fas-associated protein with death domain (FADD), although important in certain contexts, is not a prerequisite for activation of this protease.
Murphy
Brona M
BM
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
Creagh
Emma M
EM
Martin
Seamus J
SJ
D017209:Apoptosis; D029681:Arabidopsis Proteins / Q000378:metabolism; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D002384:Catalysis; D002474:Cell-Free System; D019281:Dimerization; D004789:Enzyme Activation; D044943:Fatty Acid Desaturases / Q000378:metabolism; D053804:Granzymes; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011233:Precipitin Tests; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013696:Temperature; D013997:Time Factors
D029681:Arabidopsis Proteins; D010455:Peptides; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C505407:CASP3 protein, human; C505514:CASP6 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D020169:Caspases