Toward a Comprehensive Model of Feedback Regulation in a Yeast Stress Response Pathway

Abstract

AbstractStress-Activated Protein Kinases (SAPK) protect eukaryotic cells against ischemia, hyper-osmolarity, uv-irradiation and other stressors. Dysregulation of these pathways contributes to many diseases, including Alzheimer's Disease, Amyotrophic Lateral Sclerosis and cancer. In this work, we utilize the yeast High-Osmolarity Glycerol (HOG) SAPK pathway to determine how negative and positive feedback loops regulate activity of the SAPK Hog1 in response to hyperosmotic stress. Hyperosmotic stress leads to activation of Hog1, a p38 and Jnk homologue, via two distinct signaling branches (Sho1, Sln1). Upon hyperosmotic stress, active Hog1 translocates to the nucleus, where it induces activation of stress response genes. Hog1 activation is switch-like, suggesting positive feedback. However, negative feedback leads to a graded deactivation of Hog1, allowing dose-to-duration conversion. To understand how these opposing feedback loops are coordinated, we combine biochemical and genetic approaches, live-cell microscopy, and mathematical modeling. Specifically, we use mathematical models to define a set of SAPK feedback networks that are capable of reproducing both switch-like activation and dose-to-duration encoded deactivation in response to sustained hyper-osmotic stress. We fit each model using a Monte Carlo approach for parameter estimation and objectively rank the likelihood of each feedback combination using Approximate Bayesian Computation (ABC) model selection techniques. Further analyses of the top selected models are used to generate experimentally testable predictions. Many signaling mechanisms discovered in yeast are conserved across higher eukaryotes, therefore we expect our results to aid our understanding of SAPK associated human disease.