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Systems analysis of effector caspase activation and its control by X‐linked inhibitor of apoptosis protein
Author(s) -
Rehm Markus,
Huber Heinrich J,
Dussmann Heiko,
Prehn Jochen HM
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601295
Subject(s) - xiap , inhibitor of apoptosis , effector , caspase , apoptosis , microbiology and biotechnology , caspase 3 , cleavage (geology) , caspase 9 , chemistry , caspase 7 , biology , biophysics , programmed cell death , biochemistry , paleontology , fracture (geology)
Activation of effector caspases is a final step during apoptosis. Single‐cell imaging studies have demonstrated that this process may occur as a rapid, all‐or‐none response, triggering a complete substrate cleavage within 15 min. Based on biochemical data from HeLa cells, we have developed a computational model of apoptosome‐dependent caspase activation that was sufficient to remodel the rapid kinetics of effector caspase activation observed in vivo . Sensitivity analyses predicted a critical role for caspase‐3‐dependent feedback signalling and the X‐linked‐inhibitor‐of‐apoptosis‐protein (XIAP), but a less prominent role for the XIAP antagonist Smac. Single‐cell experiments employing a caspase fluorescence resonance energy transfer substrate verified these model predictions qualitatively and quantitatively. XIAP was predicted to control this all‐or‐none response, with concentrations as high as 0.15 μM enabling, but concentrations >0.30 μM significantly blocking substrate cleavage. Overexpression of XIAP within these threshold concentrations produced cells showing slow effector caspase activation and submaximal substrate cleavage. Our study supports the hypothesis that high levels of XIAP control caspase activation and substrate cleavage, and may promote apoptosis resistance and sublethal caspase activation in vivo .