anna_paper.pdf (2.85 MB)
Download file

Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform

Download (2.85 MB)
journal contribution
posted on 19.01.2022, 17:56 authored by Anna MatveevaAnna Matveeva, Michael Fichtner, Katherine McAllister, Christopher McCann, Marc SturrockMarc Sturrock, Daniel B Longley, Jochen PrehnJochen Prehn
Ligand binding to death receptors activates apoptosis in cancer cells. Stimulation of death receptors results in the formation of intracellular multiprotein platforms that either activate the apoptotic initiator Caspase-8 to trigger cell death, or signal through kinases to initiate inflammatory and cell survival signalling. Two of these platforms, the Death-Inducing Signalling Complex (DISC) and the RIPoptosome, also initiate necroptosis by building filamentous scaffolds that lead to the activation of mixed lineage kinase domain-like pseudokinase. To explain cell decision making downstream of death receptor activation, we developed a semi-stochastic model of DISC/RIPoptosome formation. The model is a hybrid of a direct Gillespie stochastic simulation algorithm for slow assembly of the RIPoptosome and a deterministic model of downstream caspase activation. The model explains how alterations in the level of death receptor-ligand complexes, their clustering properties and intrinsic molecular fluctuations in RIPoptosome assembly drive heterogeneous dynamics of Caspase- 8 activation. The model highlights how kinetic proofreading leads to heterogeneous cell responses and results in fractional cell killing at low levels of receptor stimulation. It reveals that the noise in Caspase-8 activation-exclusively caused by the stochastic molecular assembly of the DISC/RIPoptosome platform-has a key function in extrinsic apoptotic stimuli recognition.

Funding

Science Foundation Ireland (http://www.sfi.ie/, SFI 14/IA/2582)

History

Comments

The original article is available at https://journals.plos.org/

Published Citation

Matveeva A. et al. Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform. PLoS Comput Biol. 2019 ;15(9):e1007374

Publication Date

25 September 2019

PubMed ID

31553717

Department/Unit

  • Centre for Systems Medicine
  • Physiology and Medical Physics

Research Area

  • Cancer
  • Immunity, Infection and Inflammation
  • Neurological and Psychiatric Disorders

Publisher

Public Library of Science (PLoS)

Version

  • Published Version (Version of Record)