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

Danilo R Diedrichs; Javier A Gomez; Chun-Sing Huang; D Thomas Rutkowski; Rodica Curtu

doi:10.1091/mbc.E17-09-0565

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

Journal article

Open access

Peer reviewed

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

Danilo R Diedrichs, Javier A Gomez, Chun-Sing Huang, D Thomas Rutkowski and Rodica Curtu

Molecular biology of the cell, Vol.29(12), pp.1502-1517

06/15/2018

DOI: 10.1091/mbc.E17-09-0565

PMCID: PMC6014097

PMID: 29668363

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Abstract

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.

Reproducibility of Results

Animals

Embryo, Mammalian - cytology

Models, Biological

Computer Simulation

Gene Deletion

Mice

Unfolded Protein Response

Vertebrates - metabolism

Fibroblasts - metabolism

Details

Title: Subtitle: A data-entrained computational model for testing the regulatory logic of the vertebrate unfolded protein response
Creators: Danilo R Diedrichs - Department of Mathematics, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242
Javier A Gomez - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242
Chun-Sing Huang - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242
D Thomas Rutkowski - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Rodica Curtu - Department of Mathematics, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242
Resource Type: Journal article
Publication Details: Molecular biology of the cell, Vol.29(12), pp.1502-1517
DOI: 10.1091/mbc.E17-09-0565
PMID: 29668363
PMCID: PMC6014097
NLM abbreviation: Mol Biol Cell
ISSN: 1059-1524
eISSN: 1939-4586
Publisher: American Society for Cell Biology; United States
Grant note: T32 GM067795 / NIGMS NIH HHS R01 GM115424 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 06/15/2018
Academic Unit: Anatomy and Cell Biology; Iowa Neuroscience Institute; Mathematics; Internal Medicine
Record Identifier: 9984070857102771

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