Abstract
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.
Highlights
Apoptotic signalling cascades are designed to irreversibly lead to cell death once specific death thresholds are overcome [1,2]
Most of them signal through flexible multiprotein platforms to either activate apoptotic or necroptotic cell death, or propagate cell survival and pro-inflammatory signals
We focused our study on the role of dynamic assembly and composition of these platforms in the initiation of cell death at the single cell level
Summary
Apoptotic signalling cascades are designed to irreversibly lead to cell death once specific death thresholds are overcome [1,2]. This may lead to the activation of other forms of cell death or escape from cell death altogether. Death ligands (DL) bind to death receptors (DR) at the plasma membrane and have been developed as novel cancer therapeutics. Several studies have shown that while binding of DLs to DRs can induce apoptosis, not all cells will respond to DR stimulation with cell death, and only a fraction of the cell population will undergo apoptosis even if DLs bind at death-inducing concentrations [2,3,4,5,6] (Fig 1A). In vivo studies have shown that fractional death resistance has no direct association with the amount of DRs expressed on the plasma membrane [7,8]. Cell signalling activated by extrinsic ‘death’ signals is rather encoded downstream of receptor binding
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