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Updated: Jan 19, 2026
Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
Published on: March 5, 2018
Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the
Anna Matveeva1,2, Michael Fichtner1,2, Katherine McAllister3
1Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
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.
Insights
A new model explains how cancer cells decide between life and death signaling pathways after death receptor activation. Molecular noise in protein complex formation drives cell fate decisions and fractional cancer cell killing.
Area of Science:
- Cellular biology
- Molecular signaling
- Computational modeling
Background:
- Death receptors initiate apoptosis or inflammatory signaling via multiprotein platforms like DISC and RIPoptosome.
- These platforms can also trigger necroptosis, a programmed cell death pathway.
- Understanding cell fate decisions downstream of death receptors is crucial for cancer therapy.
Purpose of the Study:
- To develop a computational model explaining cell decision-making following death receptor activation.
- To investigate the role of DISC/RIPoptosome formation dynamics in cell fate determination.
- To elucidate how molecular noise influences apoptotic signaling and cell killing.
Main Methods:
- Developed a hybrid semi-stochastic model combining Gillespie simulation and deterministic approaches.
- Modeled the formation of the Death-Inducing Signalling Complex (DISC) and RIPoptosome.
- Analyzed the dynamics of Caspase-8 activation and its relationship to receptor stimulation levels.
Main Results:
- The model explains heterogeneous Caspase-8 activation dynamics driven by receptor-ligand levels, clustering, and RIPoptosome assembly fluctuations.
- Kinetic proofreading and molecular noise in platform assembly lead to varied cell responses and fractional cell killing.
- Stochastic DISC/RIPoptosome assembly is essential for recognizing extrinsic apoptotic stimuli.
Conclusions:
- Molecular noise in DISC/RIPoptosome formation plays a critical role in cell fate decisions after death receptor stimulation.
- The model provides insights into how cancer cells exhibit heterogeneous responses to apoptotic stimuli.
- This understanding can inform strategies for enhancing cancer cell death induction.
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