A data-entrained computational model for testing the regulatory logic of the vertebrate unfolded protein response

The vertebrate unfolded protein response (UPR) is characterized by multiple interacting nodes among its three pathways, yet the logic underlying this regulatory complexity is unclear. To begin to address this issue, we created a computational model of the vertebrate UPR that was entrained upon and t...

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Bibliographic Details
Published inMolecular biology of the cell Vol. 29; no. 12; pp. 1502 - 1517
Main Authors Diedrichs, Danilo R, Gomez, Javier A, Huang, Chun-Sing, Rutkowski, D Thomas, Curtu, Rodica
Format Journal Article
LanguageEnglish
Published United States The American Society for Cell Biology 15.06.2018
SeriesA Highlights from
Subjects
Animals
Computer Simulation
Embryo, Mammalian - cytology
Fibroblasts - metabolism
Gene Deletion
Mice
Models, Biological
Reproducibility of Results
Unfolded Protein Response
Vertebrates - metabolism
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Summary:The vertebrate unfolded protein response (UPR) is characterized by multiple interacting nodes among its three pathways, yet the logic underlying this regulatory complexity is unclear. To begin to address this issue, we created a computational model of the vertebrate UPR that was entrained upon and then validated against experimental data. As part of this validation, the model successfully predicted the phenotypes of cells with lesions in UPR signaling, including a surprising and previously unreported differential role for the eIF2α phosphatase GADD34 in exacerbating severe stress but ameliorating mild stress. We then used the model to test the functional importance of a feedforward circuit within the PERK/CHOP axis and of cross-regulatory control of BiP and CHOP expression. We found that the wiring structure of the UPR appears to balance the ability of the response to remain sensitive to endoplasmic reticulum stress and to be deactivated rapidly by improved protein-folding conditions. This model should serve as a valuable resource for further exploring the regulatory logic of the UPR.
Bibliography:Present address: Department of Mathematics and Computer Science, Wheaton College, Wheaton, IL 60187.
These authors contributed equally to this work.
Author contributions: D.T.R. and R.C. conceived and designed the study; D.R.D. and R.C. were responsible for creation, parameterization, and refinement of the model; J.A.G., C.-S.H., and D.T. generated experimental data; J.A.G. and R.C. performed in silico experiments; D.R.D., J.A.G., D.T.R., and R.C. wrote the manuscript. All authors read and approved the manuscript.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E17-09-0565