Bistability in Apoptosis by Receptor Clustering

TL;DR

This paper presents a mathematical model demonstrating how receptor clustering induces bistability in apoptosis, providing insights into cell death decision mechanisms and the role of receptor dynamics in signal processing.

Contribution

The study introduces a novel mathematical model showing how Fas receptor clustering leads to bistability and irreversible cell death decisions, expanding understanding of apoptosis regulation.

Findings

Receptor clustering induces bistability in apoptosis signaling.

Hysteresis provides a mechanism for robust cell fate decisions.

Receptor pre-association enhances irreversible bistability.

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 in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.