bistability in apoptosis by receptor clustering双稳态的凋亡受体集群.pdf

Bistability in Apoptosis by Receptor Clustering 1 2 Kenneth L. Ho *, Heather A. Harrington 1 Courant Institute of Mathematical Sciences and Program in Computational Biology, New York University, New York, New York, United States of America, 2 Department of Mathematics and Centre for Integrative Systems Biology at Imperial College, Imperial College London, London, United Kingdom Abstract 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