A minimal titration model of the mammalian dynamical heat shock response

Abstract

Environmental stress, such as oxidative or heat stress, induces the activation of the heat shock response (HSR) and leads to an increase in the heat shock proteins (HSPs) level. These HSPs act as molecular chaperones to maintain cellular proteostasis. Controlled by highly intricate regulatory mechanisms, having stress-induced activation and feedback regulations with multiple partners, the HSR is still incompletely understood. In this context, we propose a minimal molecular model for the gene regulatory network of the HSR that reproduces quantitatively different heat shock experiments both on heat shock factor 1 (HSF1) and HSPs activities. This model, which is based on chemical kinetics laws, is kept with a low dimensionality without altering the biological interpretation of the model dynamics. This simplistic model highlights the titration of HSF1 by chaperones as the guiding line of the network. Moreover, by a steady states analysis of the network, three different temperature stress regimes appear: normal, acute, and chronic, where normal stress corresponds to pseudo thermal adaption. The protein triage that governs the fate of damaged proteins or the different stress regimes are consequences of the titration mechanism. The simplicity of the present model is of interest in order to study detailed modelling of cross regulation between the HSR and other major genetic networks like the cell cycle or the circadian clock.

Dynamics of Heat Shock Detection and Response in the Intestine ofCaenorhabditis elegans

“…In contrast, models of the heat shock response in HeLA cells rely on lower resolution experimental data . While some of these models explicitly account for multiple processes in great detail (Abravaya et al, 1991), it has been argued that a minimal model that limits the number of degrees of freedom and uses a coarse-grained description of the underlying molecular processes suffices to explain these data (Sivéry et al, 2016). In this paper, we demonstrated that a favorable combination of highresolution experimental data and a minimal model can help in uncovering the essential determinants of the HSR dynamics.…”

“…Previous models that place HSF-1 titration by HSPs at the center of HSR regulation identified three operating regimes of HSR and related them with normal, acute, and chronic stress conditions (Sivéry et al, 2016;Sriram et al, 2012). These three regimes are characterized by inactivation, partial activation, or saturation of HSP promoters by HSF-1, respectively.…”

Protein level variability determines phenotypic heterogeneity in proteotoxic stress response

“…In a minimal description HSRN involves three different species: (i) MisFolded proteins (MFP) that are heat-induced and (ii) HSP which helps to refold MFP and (iii) HSF1 that promotes transcription of HSP. The dynamics of the network is mainly regulated by two complexes that both involve the chaperon HSP (Sivéry et al , 2016): HSPs titrate the MFP on the one hand and its own transcription factor (HSF1) on the other. Our model accounts for the temporal evolution of copy number of four molecular species (MFP; HSP mRNA; HSF1; HSP).…”

“…The heat stress cellular response dynamic is mainly regulated by two complexes that both involve the chaperone proteins HSP (Sivéry et al , 2016). HSPs titrate the misfolded proteins, on the one hand, and its own transcription factor (HSF1) on the other.…”

“…The Heat Shock Response Network (HSRN) in the cytosol, together with the unfolded protein response in the endoplasmic reticulum, is essential for maintaining the proteome integrity (Morimoto, 2012). HSRN displays ultrasensitivity due to protein sequestration mechanism (Buchler and Cross, 2009; Sivéry et al , 2016). Several proteotoxic stresses, such as oxidation or heat, trigger HSRN which induces the transcription of Heat Shock Proteins (HSPs) via activation of Heat Shock Factor 1 (HSF1) transcription factor.…”