Modeling a snap-action, variable-delay switch controlling extrinsic cell death
John G Albeck1, John M Burke, Sabrina L Spencer
1Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
When exposed to tumor necrosis factor (TNF) or TNF-related apoptosis-inducing ligand (TRAIL), a closely related death ligand and investigational therapeutic, cells enter a protracted period of variable duration in which only upstream initiator caspases are active. A subsequent and sudden transition marks activation of the downstream effector caspases that rapidly dismantle the cell. Thus, extrinsic apoptosis is controlled by an unusual variable-delay, snap-action switch that enforces an unambiguous choice between life and death. To understand how the extrinsic apoptosis switch functions in quantitative terms, we constructed a mathematical model based on a mass-action representation of known reaction pathways. The model was trained against experimental data obtained by live-cell imaging, flow cytometry, and immunoblotting of cells perturbed by protein depletion and overexpression. The trained model accurately reproduces the behavior of normal and perturbed cells exposed to TRAIL, making it possible to study switching mechanisms in detail. Model analysis shows, and experiments confirm, that the duration of the delay prior to effector caspase activation is determined by initiator caspase-8 activity and the rates of other reactions lying immediately downstream of the TRAIL receptor. Sudden activation of effector caspases is achieved downstream by reactions involved in permeabilization of the mitochondrial membrane and relocalization of proteins such as Smac. We find that the pattern of interactions among Bcl-2 family members, the partitioning of Smac from its binding partner XIAP, and the mechanics of pore assembly are all critical for snap-action control.
Insights
Extrinsic apoptosis uses a variable-delay, snap-action switch controlled by initiator caspases. This switch, modeled mathematically, determines cell life or death following tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exposure.
Area of Science:
- Cellular biology
- Molecular mechanisms of apoptosis
- Mathematical modeling of biological systems
Background:
- Extrinsic apoptosis involves a delay before effector caspases activate, leading to cell death.
- This process is triggered by death ligands like tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL).
- The precise quantitative mechanisms governing this variable-delay, snap-action switch remain incompletely understood.
Purpose of the Study:
- To quantitatively understand the mechanisms controlling the extrinsic apoptosis switch.
- To investigate the roles of initiator and effector caspase activities in determining cell fate.
- To identify key molecular interactions critical for the switch's snap-action control.
Main Methods:
- Construction of a mathematical model based on mass-action principles of known reaction pathways.
- Training the model against experimental data from live-cell imaging, flow cytometry, and immunoblotting.
- Perturbing cellular systems via protein depletion and overexpression to validate model predictions.
Main Results:
- The trained mathematical model accurately reproduces cellular responses to TRAIL in both normal and perturbed cells.
- Initiator caspase-8 activity and downstream reaction rates dictate the delay period before effector caspase activation.
- Mitochondrial membrane permeabilization, Smac relocalization, and Bcl-2 family interactions are crucial for snap-action control.
Conclusions:
- The extrinsic apoptosis pathway functions as a precise variable-delay, snap-action switch.
- Initiator caspase activity and mitochondrial pathway engagement are key determinants of apoptosis timing and execution.
- Interactions among Bcl-2 family proteins, Smac, and XIAP are critical for the switch's rapid and decisive action.
Related Concept Videos
01:30Overview of Cell Death
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
01:30Apoptosis
01:17The Extrinsic Apoptotic Pathway
01:31The Intrinsic Apoptotic Pathway
01:18Autophagic Cell Death
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and...
01:14Design Example: Frog Muscle Response
When the switch connecting the RL circuit is closed, a brief muscle contraction is observed. This is because, at a steady state, the inductor acts like a short...