On the cover, art patrons observe an exhibit contrasting a healthy ER with one in which regulation of protein folding has been disrupted, causing swelling of the ER lumen. (Artwork: Mariana Schnell and Santiago Schnell, University of Michigan; TEM images reproduced with permission from Proc Natl Acad Sci USA 111 [2014], E582–E591, Fig. 5, Panel A

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

On the cover, art patrons observe an exhibit contrasting a healthy ER with one in which regulation of protein folding has been disrupted, causing swelling of the ER lumen. (Artwork: Mariana Schnell and Santiago Schnell, University of Michigan; TEM images reproduced with permission from Proc Natl Acad Sci USA 111 [2014], E582–E591, Fig. 5, Panel A

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

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.

Publication
MOLECULAR BIOLOGY OF THE CELL 29, 3052-3062