Death ligand concentration and the membrane proximal signaling module regulate the type 1/ type 2 choice in apoptotic death signaling

TL;DR

This study uses computational modeling to explore how death ligand levels and membrane signaling influence the decision between type 1 and type 2 apoptosis pathways, revealing mechanisms behind cell variability and implications for disease therapies.

Contribution

It provides new mechanistic insights into DISC formation and caspase activation, highlighting how ligand concentration and feedback loops determine apoptosis pathway choice.

Findings

Higher death ligand levels favor type 1 activation

Caspase 6 feedback influences pathway decision

Cell-to-cell variability impacts apoptosis outcomes

Abstract

Apoptotic death pathways are frequently activated by death ligand induction and subsequent activation of the membrane proximal signaling module. Death receptors cluster upon binding to death ligands, leading to formation of a membrane proximal death-inducing-signaling-complex (DISC). In this membrane proximal signalosome, initiator caspases (caspase 8) are processed resulting in activation of both type 1 and type 2 pathways of apoptosis signaling. How the type 1/type 2 choice is made is an important question in the systems biology of apoptosis signaling. In this study, we utilize a Monte Carlo based in silico approach to elucidate the role of membrane proximal signaling module in the type 1/type 2 choice of apoptosis signaling. Our results provide crucial mechanistic insights into the formation of DISC signalosome and caspase 8 activation. Increased concentration of death ligands was shown to correlate with increased type 1 activation. We also study the caspase 6 mediated system level feedback activation of apoptosis signaling and its role in the type 1/type 2 choice. Our results clarify the basis of cell-to-cell stochastic variability in apoptosis activation and ramifications of this issue is further discussed in the context of therapies for cancer and neurodegenerative disorders.