Synergies and trade-offs in the heat shock response mechanism
- 1Department of Physics, Indian Institute of Technology Jammu, Jammu, India
- 2Amrita School of Artificial Intelligence, Amrita Vishwa Vidyapeetham, Coimbatore, India
- 3Department of Biosciences and Bioengineering, Indian Institute of Technology Jammu, Jammu, India
Abstract
E. coli relies on the heat shock response (HSR) to preserve protein homeostasis under stress, through three feedback modules: feedforward translational control, chaperone-mediated sequestration and targeted degradation. Although previous studies have highlighted how this layered architecture ensures rapid and robust protection compared to simpler designs, not much attention is paid to how these modules interact. Moreover, how do interactions among the three modules balance performance trade-offs, where gains in one module may come at the expense of another, yet together yield an optimal overall response? We address this using a mathematical model that integrates protein folding with σ32 regulation. We show that the feedback modules both cooperate and compete, giving rise to nonmonotonic dynamics that govern HSR performance. Specifically, increasing feedforward strength does accelerate response, but beyond a threshold, despite increasing chaperone levels, it paradoxically slows recovery. Similarly, while sequestration enhances relative chaperone production and per-chaperone efficiency, when excessive, it traps σ32 in inactive complexes, prolonging recovery and delaying shutdown. Mapping the parameter space reveals regimes of synergy as well as trade-offs between speed and efficiency, with wild-type parameters lying near the optimal region. These results reveal design principles that produces a robust and efficient heat shock response. Author summary: Proteins must adopt a specific three-dimensional structure to perform their function within the cell. However, they can misfold into non-functional states, especially under stress conditions such as elevated temperature. Misfolded proteins can accumulate and disrupt cellular processes, making their timely repair essential for cell survival. To manage this, cells employ the heat shock response, a conserved regulatory system that maintains protein homeostasis under stress. In Escherichia coli, this response is controlled by three interconnected modules: rapid production of the key regulator σ32, its inactivation through chaperone binding, and its degradation. Together, these modules enable a rapid response while ensuring timely recovery once normal conditions are restored. We use a mathematical model to examine how these modules interact. Because they share common molecular components, particularly σ32 and chaperones, and therefore do not act independently. Our analysis reveals that interactions between regulatory modules can be cooperative or competing, depending on the relative strength of the modules. Such interactions generate nonmonotonic behavior and trade-offs among recovery speed, efficient chaperone utilization, and timely shutdown of the stress response. We also identify an optimal operating regime in which the combined regulation balances competing demands, revealing general design principles of stress adaptation.
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BibTeX
@article{chauhan2026synergies,
title = {{Synergies and trade-offs in the heat shock response mechanism}},
author = {Rupal Chauhan and Biswajit Das and Ajeet K. Sharma},
journal = {PLOS Computational Biology},
year = {2026},
month = sep,
doi = {10.1371/journal.pcbi.1014729},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014729},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Synergies and trade-offs in the heat shock response mechanism
AU - Rupal Chauhan
AU - Biswajit Das
AU - Ajeet K. Sharma
PY - 2026
DA - 2026/09/02
JO - PLOS Computational Biology
DO - 10.1371/journal.pcbi.1014729
UR - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014729
AB - E. coli relies on the heat shock response (HSR) to preserve protein homeostasis under stress, through three feedback modules: feedforward translational control, chaperone-mediated sequestration and targeted degradation. Although previous studies have highlighted how this layered architecture ensures rapid and robust protection compared to simpler designs, not much attention is paid to how these modules interact. Moreover, how do interactions among the three modules balance performance trade-offs, where gains in one module may come at the expense of another, yet together yield an optimal overall response? We address this using a mathematical model that integrates protein folding with σ32 regulation. We show that the feedback modules both cooperate and compete, giving rise to nonmonotonic dynamics that govern HSR performance. Specifically, increasing feedforward strength does accelerate response, but beyond a threshold, despite increasing chaperone levels, it paradoxically slows recovery. Similarly, while sequestration enhances relative chaperone production and per-chaperone efficiency, when excessive, it traps σ32 in inactive complexes, prolonging recovery and delaying shutdown. Mapping the parameter space reveals regimes of synergy as well as trade-offs between speed and efficiency, with wild-type parameters lying near the optimal region. These results reveal design principles that produces a robust and efficient heat shock response. Author summary: Proteins must adopt a specific three-dimensional structure to perform their function within the cell. However, they can misfold into non-functional states, especially under stress conditions such as elevated temperature. Misfolded proteins can accumulate and disrupt cellular processes, making their timely repair essential for cell survival. To manage this, cells employ the heat shock response, a conserved regulatory system that maintains protein homeostasis under stress. In Escherichia coli, this response is controlled by three interconnected modules: rapid production of the key regulator σ32, its inactivation through chaperone binding, and its degradation. Together, these modules enable a rapid response while ensuring timely recovery once normal conditions are restored. We use a mathematical model to examine how these modules interact. Because they share common molecular components, particularly σ32 and chaperones, and therefore do not act independently. Our analysis reveals that interactions between regulatory modules can be cooperative or competing, depending on the relative strength of the modules. Such interactions generate nonmonotonic behavior and trade-offs among recovery speed, efficient chaperone utilization, and timely shutdown of the stress response. We also identify an optimal operating regime in which the combined regulation balances competing demands, revealing general design principles of stress adaptation.
SN - 1553-7358
ER -