Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Mechanistic Modeling and Analysis of the Mammalian Unfolded Protein Response

Anirikh Chakrabarti, Lina Aboulmouna, Jeffrey Varner
doi: https://doi.org/10.1101/060020
Anirikh Chakrabarti
1Cornell University, School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lina Aboulmouna
2Purdue University, School of Chemical Engineering, West Lafayette, IN 47907, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jeffrey Varner
1Cornell University, School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA
2Purdue University, School of Chemical Engineering, West Lafayette, IN 47907, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

Cells monitor protein folding by an inbuilt quality-control system in which incorrectly or misfolded folded proteins are tagged for degradation or sent back through a refolding cycle. However, continued accumulation of incorrectly folded proteins triggers the Unfolded Protein Response (UPR), which attempts to re-establish folding homeostasis or commits the cell to apoptosis. In this study, we developed a family of mechanistic models of the mammalian UPR system. An ensemble of models parameters was estimated by minimizing the difference between simulations and experimental measurements using multiobjective optimization. The ensemble of model parameters was validated using cross-validation. Analysis of the model ensemble suggested the three branches of UPR fired simultaneously. However, the importance of each brach was ranked ordered in time; PERK and IRE1 were more important early, while ATF6 was important later in the response. The activity of all three branches as coordinated by the molecular chaperone BiP. Model analysis suggested that BiP feedback was critical to the overall robustness of the system. Removal of any one branch of BiP feedback, destabilized the other branches. On the other hand, removal of all nodes of BiP feedback increased the overall robustness of the system. Thus, while BiP feedback is crucial to allowing the cell to adapt to small perturbations, it also makes the system fragile and susceptible to manipulation.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Back to top
PreviousNext
Posted June 21, 2016.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Mechanistic Modeling and Analysis of the Mammalian Unfolded Protein Response
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Mechanistic Modeling and Analysis of the Mammalian Unfolded Protein Response
Anirikh Chakrabarti, Lina Aboulmouna, Jeffrey Varner
bioRxiv 060020; doi: https://doi.org/10.1101/060020
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Mechanistic Modeling and Analysis of the Mammalian Unfolded Protein Response
Anirikh Chakrabarti, Lina Aboulmouna, Jeffrey Varner
bioRxiv 060020; doi: https://doi.org/10.1101/060020

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Systems Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (4227)
  • Biochemistry (9107)
  • Bioengineering (6751)
  • Bioinformatics (23944)
  • Biophysics (12089)
  • Cancer Biology (9495)
  • Cell Biology (13740)
  • Clinical Trials (138)
  • Developmental Biology (7616)
  • Ecology (11661)
  • Epidemiology (2066)
  • Evolutionary Biology (15479)
  • Genetics (10617)
  • Genomics (14296)
  • Immunology (9462)
  • Microbiology (22792)
  • Molecular Biology (9078)
  • Neuroscience (48888)
  • Paleontology (355)
  • Pathology (1479)
  • Pharmacology and Toxicology (2565)
  • Physiology (3823)
  • Plant Biology (8308)
  • Scientific Communication and Education (1467)
  • Synthetic Biology (2290)
  • Systems Biology (6172)
  • Zoology (1297)