Malfunctions in the folding state of critical proteins have been linked with cancer, diabetes and other diseases. Proteins requiring complex post-translational modification are processed in the Endoplasmic Reticulum (ER). Cells monitor protein folding by an inbuilt quality-control system involving both the ER and the Golgi apparatus. Incorrectly folded proteins are tagged for degradation or sent back through a refolding cycle. Accumulation of incorrectly folded proteins can trigger a cascade of events, termed the Unfolded Protein Response (UPR). In this study, we developed a mathematical model of UPR, which was composed of a system of ordinary differential equations. Model parameters (1090 kinetic parameters and 636 initial conditions) were estimated by comparing simulations with a family of training constraints. Using a novel multi-objective optimization framework called POET combined with a cross-validation scheme, we generated a population of models consistent with the experimental data. Model analysis revealed the importance of key species like BiP, HSP40, XBP1, BAD and CHOP. BiP release from ER stress transducers and BiP regulation were the most critical aspects of UPR initiation. Regulation of XBP1, CHOP and ATF4 were critical to the UPR response midstream. Regulation of Bcl2 and BAD were the most important aspect of UPR mediated apoptosis. Taken together, we demonstrated that modeling could be used to understand key structural elements of UPR, despite model uncertainty. Understanding the architecture of this stress pathway could help us understand the design principles governing other stress related networks, e.g., hypoxia. Thus, while the current study was limited to UPR, the general strategy could be extended to other stress networks relevant to human health.
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Modeling Eukaryotic Unfolded Protein Response and Its Role In Cellular Stress
Malfunctions in the folding state of critical proteins have been linked with cancer, diabetes and other diseases. Proteins requiring complex post-translational modification are processed in the Endoplasmic Reticulum (ER). Cells monitor protein folding by an inbuilt quality-control system involving both the ER and the Golgi apparatus. Incorrectly folded proteins are tagged for degradation or sent back through a refolding cycle. Accumulation of incorrectly folded proteins can trigger a cascade of events, termed the Unfolded Protein Response (UPR). In this study, we developed a mathematical model of UPR, which was composed of a system of ordinary differential equations. Model parameters (1090 kinetic parameters and 636 initial conditions) were estimated by comparing simulations with a family of training constraints. Using a novel multi-objective optimization framework called POET combined with a cross-validation scheme, we generated a population of models consistent with the experimental data. Model analysis revealed the importance of key species like BiP, HSP40, XBP1, BAD and CHOP. BiP release from ER stress transducers and BiP regulation were the most critical aspects of UPR initiation. Regulation of XBP1, CHOP and ATF4 were critical to the UPR response midstream. Regulation of Bcl2 and BAD were the most important aspect of UPR mediated apoptosis. Taken together, we demonstrated that modeling could be used to understand key structural elements of UPR, despite model uncertainty. Understanding the architecture of this stress pathway could help us understand the design principles governing other stress related networks, e.g., hypoxia. Thus, while the current study was limited to UPR, the general strategy could be extended to other stress networks relevant to human health.