Control Strategies for the Regulation of the Eukaryotic Heat Shock Response

Elevated temperatures cause proteins in living cells to misfold. They start forming larger and larger aggregates that call eventually lead to the cell's death. The heat shock response is an evolutionary well conserved cellular response to massive protein misfolding and it is driven by the need to keep the level of misfolded proteins under control. We consider in this paper a recently proposed new molecular model for the heat shock response in enkaryotes, consisting of a temperature-induced activation mechanism, chaperoning of misfolded proteins and self-regulation of the chaperon synthesis. We take in this paper a control driven approach to studying this regulatory network. We modularize the network by identifying its main functional modules. We distinguish three main feedback loops. The main question we are addressing is why is this level of complexity needed for implementing what could in principle also be achieved with art open-loop design. We answer the question by comparing the numerical behavior of various knockdown mutants where one or more feedback loops are missing. We also discuss a new approach for a biologically-unbiased model comparison.