How to design an optimal sensor network for the unfolded protein response

Mol Biol Cell. 2018 Dec 1;29(25):3052-3062. doi: 10.1091/mbc.E18-01-0060. Epub 2018 Sep 26.

Abstract

Cellular protein homeostasis requires continuous monitoring of stress in the endoplasmic reticulum (ER). Stress-detection networks control protein homeostasis by mitigating the deleterious effects of protein accumulation, such as aggregation and misfolding, with precise modulation of chaperone production. Here, we develop a coarse model of the unfolded protein response in yeast and use multi-objective optimization to determine which sensing and activation strategies optimally balance the trade-off between unfolded protein accumulation and chaperone production. By comparing a stress-sensing mechanism that responds directly to the level of unfolded protein in the ER to a mechanism that is negatively regulated by unbound chaperones, we show that chaperone-mediated sensors are more efficient than sensors that detect unfolded proteins directly. This results from the chaperone-mediated sensor having separate thresholds for activation and deactivation. Finally, we demonstrate that a sensor responsive to both unfolded protein and unbound chaperone does not further optimize homeostatic control. Our results suggest a strategy for designing stress sensors and may explain why BiP-mitigated ER stress-sensing networks have evolved.

MeSH terms

  • Biosensing Techniques
  • Endoplasmic Reticulum / metabolism
  • Homeostasis
  • Models, Biological
  • Molecular Chaperones / metabolism*
  • Software
  • Stress, Physiological
  • Unfolded Protein Response*
  • Yeasts

Substances

  • Molecular Chaperones