Abstract
Autophagy and apoptosis are cellular processes that regulate cell survival and death, the former by eliminating dysfunctional components in the cell, the latter by programmed cell death. Stress signals can induce either process, and it is unclear how cells ‘assess’ cellular damage and make a ‘life’ or ‘death’ decision upon activating autophagy or apoptosis. A computational model of coupled apoptosis and autophagy is built here to analyze the underlying signaling and regulatory network dynamics. The model explains the experimentally observed differential deployment of autophagy and apoptosis in response to various stress signals. Autophagic response dominates at low-to-moderate stress; whereas the response shifts from autophagy (graded activation) to apoptosis (switch-like activation) with increasing stress intensity. The model reveals that cytoplasmic Ca2+ acts as a rheostat that fine-tunes autophagic and apoptotic responses. A G-protein signaling-mediated feedback loop maintains cytoplasmic Ca2+ level, which in turn governs autophagic response through an AMP-activated protein kinase (AMPK)-mediated feedforward loop. Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ) emerges as a determinant of the competing roles of cytoplasmic Ca2+ in autophagy regulation. The study demonstrates that the proposed model can be advantageously used for interrogating cell regulation events and developing pharmacological strategies for modulating cell decisions.
Highlights
Autophagy is a cytoprotective homeostatic process in which cells digest their own cytoplasmic constituents or organelles, and degrade them in the lysosomes, in response to diverse stress stimuli[1]
The model is composed of five modules, which includes the major signaling cascades activated in response to nutritional, genotoxic, and endoplasmic reticulum (ER) stresses (Fig. 1a)
The system is composed of 94 components, including the different activation, binding or localizations states of involved proteins, and the dynamics of this system is represented by a system of ordinary differential equations (ODEs)
Summary
Autophagy is a cytoprotective homeostatic process in which cells digest their own cytoplasmic constituents or organelles, and degrade them in the lysosomes, in response to diverse stress stimuli[1]. A database has been developed[10] for mining the network of protein-protein interactions as well as transcription factors and miRNAs implicated in autophagy regulation. While this database is a valuable resource that provides information on autophagy components and regulators, there is a need to build in parallel models and methods that can leverage existing data and assist in making mechanistic inferences on the dynamics of autophagic interactions. The model enables the rapid assessment of the effect of a series of drugs on the onset and development of autophagy or apoptosis, under different stress conditions
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