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.
Funding
Science Foundation Ireland (http://www.sfi.ie/, SFI 14/IA/2582)
History
Comments
The original article is available at https://journals.plos.org/
Published Citation
Matveeva A. et al. Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform. PLoS Comput Biol. 2019 ;15(9):e1007374