title: The caspase-8 dimerization/dissociation balance is a highly potent regulator of caspase-8, -3, -6 signaling.
abstract: Apoptosis is driven by positive feedback activation between aspartate-specific cysteinyl proteases (caspases). These feedback loops ensure the swift and efficient elimination of cells upon initiation of apoptosis execution. At the same time, the signaling network must be insensitive to erroneous, mild caspase activation to avoid unwanted, excessive cell death. Sublethal caspase activation in fact was shown to be a requirement for the differentiation of multiple cell types but might also occur accidentally during short, transient cellular stress conditions. Here we carried out an in silico comparison of the molecular mechanisms that so far have been identified to impair the amplification of caspase activities via the caspase-8, -3, -6 loop. In a systems model resembling HeLa cervical cancer cells, the dimerization/dissociation balance of caspase-8 potently suppressed the amplification of caspase responses, surprisingly outperforming or matching known caspase-8 and -3 inhibitors such as bifunctional apoptosis repressor or x-linked inhibitor of apoptosis protein. These findings were further substantiated in global sensitivity analyses based on combinations of protein concentrations from the sub- to superphysiological range to screen the full spectrum of biological variability that can be expected within cell populations and between distinct cell types. Additional modeling showed that the combined effects of x-linked inhibitor of apoptosis protein and caspase-8 dimerization/dissociation processes can also provide resistance to larger inputs of active caspases. Our study therefore highlights a central and so far underappreciated role of caspase-8 dimerization/dissociation in avoiding unwanted cell death by lethal amplification of caspase responses via the caspase-8, -3, -6 loop.
authors: From the Department of Physiology and Medical Physics, Dublin 2, Ireland; Systems Biology Group, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors: Maximilian L
authors: ML
authors: Würstle
authors: From the Department of Physiology and Medical Physics, Dublin 2, Ireland; Systems Biology Group, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors: Maike A
authors: MA
authors: Laussmann
authors: From the Department of Physiology and Medical Physics, Dublin 2, Ireland; Systems Biology Group, Royal College of Surgeons in Ireland, Dublin 2, Ireland. Electronic address: mrehm@rcsi.ie.
authors: Markus
authors: M
authors: Rehm
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D053178:Caspase 6 / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D055503:Protein Multimerization / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C406792:BFAR protein, human; D008565:Membrane Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C505407:CASP3 protein, human; C505514:CASP6 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8