Bistability in Apoptosis by Receptor Clustering

Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.Author Summary: Many prominent diseases, most notably cancer, arise from an imbalance between the rates of cell growth and death in the body. This is often due to mutations that disrupt a cell death program called apoptosis. Here, we focus on the extrinsic pathway of apoptotic activation which is initiated upon detection of an external death signal, encoded by a death ligand, by its corresponding death receptor. Through the tools of mathematical analysis, we find that a novel model of death ligand-receptor interactions based on recent experimental data possesses the capacity for bistability. Consequently, the model supports threshold-like switching between unambiguous life and death states; intuitively, the defining characteristic of an effective cell death mechanism. We thus highlight the role of death receptors, the first component along the apoptotic pathway, in deciding cell fate. Furthermore, the model suggests an explanation for various biologically observed phenomena, including the trimeric character of the death ligand and the tendency for death receptors to colocalize, in terms of bistability. Our work hence informs the molecular basis of the apoptotic point-of-no-return, and may influence future drug therapies against cancer and other diseases.