The apoptosome molecular timer synergises with XIAP to suppress apoptosis execution and contributes to prognosticating survival in colorectal cancer.
journal contributionposted on 08.01.2021, 13:40 by Gavin Fullstone, Tabea L Bauer, Cristiano Guttà, Manuela Salvucci, Jochen Prehn, Markus Rehm
The execution phase of apoptosis is a critical process in programmed cell death in response to a multitude of cellular stresses. A crucial component of this pathway is the apoptosome, a platform for the activation of pro-caspase 9 (PC9). Recent findings have shown that autocleavage of PC9 to Caspase 9 (C9) p35/p12 not only permits XIAP-mediated C9 inhibition but also temporally shuts down apoptosome activity, forming a molecular timer. In order to delineate the combined contributions of XIAP and the apoptosome molecular timer to apoptosis execution we utilised a systems modelling approach. We demonstrate that cooperative recruitment of PC9 to the apoptosome, based on existing PC9-apoptosome interaction data, is important for efficient formation of PC9 homodimers, autocatalytic cleavage and dual regulation by XIAP and the molecular timer across biologically relevant PC9 and APAF1 concentrations. Screening physiologically relevant concentration ranges of apoptotic proteins, we discovered that the molecular timer can prevent apoptosis execution in specific scenarios after complete or partial mitochondrial outer membrane permeabilisation (MOMP). Furthermore, its ability to prevent apoptosis is intricately tied to a synergistic combination with XIAP. Finally, we demonstrate that simulations of these processes are prognostic of survival in stage III colorectal cancer and that the molecular timer may promote apoptosis resistance in a subset of patients. Based on our findings, we postulate that the physiological function of the molecular timer is to aid XIAP in the shutdown of caspase-mediated apoptosis execution. This shutdown potentially facilitates switching to pro-inflammatory caspase-independent responses subsequent to Bax/Bak pore formation.
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - FOR2036 (MO 3226/1-1).
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy - EXC 2075 - 390740016.
Science Foundation Ireland (16/US/3301).
Associated research data filesSupplementary material available at https://doi.org/10.1038/s41418-020-0545-9. Code availability: The model has been uploaded to the data repository Zenodo under a Creative Commons Attribution 4.0 International license (10.5281/zenodo.3712773) along with setup files to replicate figures within this paper. Scripts for processing of patient data was previously made available on Zenodo (10.5281/zenodo.1162682).
CommentsThe original article is available at https://www.nature.com/
Published CitationFullstone G, Bauer TL, Guttà C, Salvucci M, Prehn JHM, Rehm M. The apoptosome molecular timer synergises with XIAP to suppress apoptosis execution and contributes to prognosticating survival in colorectal cancer. Cell Death & Differentiation. 2020;27(10):2828-2842.
Publication Date27 April 2020
- Centre for Systems Medicine
- Physiology and Medical Physics
- Published Version (Version of Record)