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PLoS Comput Biol. 2019 Sep 25;15(9):e1007374. doi: 10.1371/journal.pcbi.1007374. eCollection 2019 Sep.

Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform.

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Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Centre for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom.


Ligand binding to death receptors activates apoptosis in cancer cells. Stimulation of death receptors results in the formation of intracellular multiprotein platforms that either activate the apoptotic initiator Caspase-8 to trigger cell death, or signal through kinases to initiate inflammatory and cell survival signalling. Two of these platforms, the Death-Inducing Signalling Complex (DISC) and the RIPoptosome, also initiate necroptosis by building filamentous scaffolds that lead to the activation of mixed lineage kinase domain-like pseudokinase. To explain cell decision making downstream of death receptor activation, we developed a semi-stochastic model of DISC/RIPoptosome formation. The model is a hybrid of a direct Gillespie stochastic simulation algorithm for slow assembly of the RIPoptosome and a deterministic model of downstream caspase activation. The model explains how alterations in the level of death receptor-ligand complexes, their clustering properties and intrinsic molecular fluctuations in RIPoptosome assembly drive heterogeneous dynamics of Caspase-8 activation. The model highlights how kinetic proofreading leads to heterogeneous cell responses and results in fractional cell killing at low levels of receptor stimulation. It reveals that the noise in Caspase-8 activation-exclusively caused by the stochastic molecular assembly of the DISC/RIPoptosome platform-has a key function in extrinsic apoptotic stimuli recognition.

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Conflict of interest statement

The authors have declared that no competing interests exist.

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