1. Cell Biology
  2. Computational and Systems Biology
Download icon

Heat Shock Response: A model for handling cell stress

  1. Laura Le Breton
  2. Matthias P Mayer  Is a corresponding author
  1. DKFZ-ZMBH-Alliance, Germany
  • Cited 5
  • Views 3,461
  • Annotations
Cite this article as: eLife 2016;5:e22850 doi: 10.7554/eLife.22850


The heat shock response in yeast is regulated by the interaction between a chaperone protein and a heat shock transcription factor, and fine-tuned by phosphorylation.

Main text

Cells are subjected to frequent assaults either from their environment or as a consequence of development or disease. Such stresses – which can be caused by a range of conditions, including changes in temperature and mechanical stresses – are damaging to proteins, so cells mount the so-called heat shock response. This response is an evolutionarily conserved transcriptional program that is orchestrated in eukaryotic cells by a protein called Hsf1 (short for heat shock factor 1; Morimoto, 1998). Three copies of this protein combine to form trimers that bind to the promoters of Hsf1-dependent genes, which leads to higher levels of heat shock proteins inside the cell. These proteins include the chaperones that refold misfolded proteins or target them for degradation. Once the effects of the stress have been dealt with, cells reduce the production of heat shock proteins to normal levels.

The heat shock response has been studied for more than 30 years, mainly in yeast and animal cells, and different models have been proposed to explain it (Anckar and Sistonen, 2011). The intrinsic response model, which assumes that Hsf1 directly senses increasing temperature (and potentially other stresses), relies on Hsf1 transitioning from a monomer to a trimer (Zhong et al., 1998; Hentze et al., 2016). This model can only apply to animal cells because Hsf1 forms trimers in yeast under all conditions, even in the absence of heat shock (Sorger et al., 1987).

The chaperone titration model assumes that Hsf1 is kept inactive in unstressed cells by its interactions with chaperones; the presence of misfolded proteins then activates Hsf1 by attracting (or “titrating”) the chaperones away from Hsf1. Although there is evidence to support such a model, it was unclear which – if any – of the chaperones is the main regulator of the Hsf1 activity cycle. (Shi et al., 1998; Rabindran et al., 1994; Guo et al., 2001). In addition, Hsf1 is subject to a large number of post-translational modifications, such as phosphorylation, but the influence of these modifications on the heat shock response is a topic of controversy (Budzyński et al., 2015; Xia and Voellmy, 1997).

Now, in eLife, David Pincus and coworkers from the Whitehead Institute for Biomedical Research, Boston University and Harvard University – including Xu Zheng and Joanna Krakowiak as joint first authors – report how they have used a combination of mathematical modeling and cell biology experiments in yeast to address these issues (Zheng et al., 2016).

Initial experimental results demonstrated that a chaperone called Hsp70 – which is thought to damp down the heat shock response – binds to Hsf1 under non-stress conditions and is released upon a sudden increase in temperature. From these findings, Zheng et al. simulated how the expression of Hsf1-dependent genes changes in response to interactions between Hsp70, Hsf1 and misfolded proteins. Further support for the chaperone titration model came from experiments in which yeast cells expressed two types of Hsf1: wild-type Hsf1 and “decoy” Hsf1 (which can bind to Hsp70 but cannot activate the transcription of the Hsf1-dependent genes). These data are the strongest evidence to date that Hsp70 feedback regulates the heat shock response by directly associating with Hsf1, as happens in the chaperone titration model (Figure 1).

The chaperone titration model of the heat shock response.

Clockwise from top: The chaperone protein Hsp70 binds to the heat shock transcription factor Hsf1, repressing its transcriptional activity. Upon a sudden increase in temperature or other stresses (red lightning bolt), fewer proteins maintain their correct shape (rectangles); misfolded proteins (stars) therefore accumulate in the cell. These misfolded proteins draw Hsp70 away from Hsf1, activating its transcriptional activity. As a result, more Hsf1-dependent genes (HDG) are expressed, leading to an increase in the number of chaperones and proteases – among them Hsp70 – in the cell. The action of the chaperones and proteases ensures that proteins can be correctly folded again; this also liberates Hsp70, which can then repress Hsf1. Middle: Hyperphosphorylation of Hsf1 (the width of the triangle represents the extent of phosphorylation) partially activates Hsf1 and sensitizes the regulatory feedback circuit.

The overexpression of Hsf1 under otherwise unstressed conditions impairs the growth of yeast cells by over-activating the transcription of Hsf1-dependent genes. Elevating the levels of Hsp70 or one of its co-chaperones in such cells rescues growth and represses the transcription of Hsf1-dependent genes. In contrast, Hsp90 – a chaperone that was believed to repress Hsf1 under non-stress conditions (Duina et al., 1998; Zou et al., 1998) – had no effect on growth or the transcription of Hsf1-dependent genes in these cells. This argues against Hsp90 playing a major role in down-regulating Hsf1 activity. Thus, the effects of the down-regulation of Hsp90 or its co-chaperones on the heat shock response might be indirect in yeast.

Zheng et al. also investigated how the hyperphosphorylation of Hsf1 helps to regulate the heat shock response. They performed en masse mutations of Hsf1 by either removing all 152 potential phosphorylation sites, or mimicking phosphorylation at up to 116 sites. Unexpectedly, completely abolishing phosphorylation only mildly reduces Hsf1 activity upon heat shock, indicating that phosphorylation per se is not required to activate Hsf1. On the other hand, mimicking hyperphosphorylation activates Hsf1 even under non-stress conditions. Moreover, the activity of Hsf1 increases further upon heat shock, which means that hyperphosphorylation only partially overwrites the repression of Hsf1 by Hsp70. Phosphorylation is thus a dose-dependent mechanism for fine-tuning the activity of Hsf1 that mainly occurs after the initial phase of the heat shock response, enhancing and prolonging it. This also means that if the stress response is activated for developmental or other reasons, the cell is still able to react to acute assaults.

It will be important in the future to assess whether these findings also apply to animal Hsf1, which interacts with chaperones such as Hsp70 and Hsp90 while in its inactive monomeric form under non-stress conditions (Shi et al., 1998; Zou et al., 1998). It also remains to be discovered how these chaperones integrate with the ability of Hsf1 to directly sense stress (Zhong et al., 1998; Hentze et al., 2016).


Article and author information

Author details

  1. Laura Le Breton

    Center for Molecular Biology Heidelberg University, DKFZ-ZMBH-Alliance, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5599-3244
  2. Matthias P Mayer

    Center for Molecular Biology Heidelberg University, DKFZ-ZMBH-Alliance, Heidelberg, Germany
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7859-3112

Publication history

  1. Version of Record published: November 29, 2016 (version 1)


© 2016, Le Breton et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 3,461
    Page views
  • 403
  • 5

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Physics of Living Systems
    Jacopo Di Russo et al.
    Research Article

    Nanometer-scale properties of the extracellular matrix influence many biological processes, including cell motility. While much information is available for single-cell migration, to date, no knowledge exists on how the nanoscale presentation of extracellular matrix receptors influences collective cell migration. In wound healing, basal keratinocytes collectively migrate on a fibronectin-rich provisional basement membrane to re-epithelialize the injured skin. Among other receptors, the fibronectin receptor integrin α5β1 plays a pivotal role in this process. Using a highly specific integrin α5β1 peptidomimetic combined with nanopatterned hydrogels, we show that keratinocyte sheets regulate their migration ability at an optimal integrin α5β1 nanospacing. This efficiency relies on the effective propagation of stresses within the cell monolayer independent of substrate stiffness. For the first time, this work highlights the importance of extracellular matrix receptor nanoscale organization required for efficient tissue regeneration.

    1. Cell Biology
    Lisa M Strong et al.
    Research Article Updated

    Autophagy is a cellular process that degrades cytoplasmic cargo by engulfing it in a double-membrane vesicle, known as the autophagosome, and delivering it to the lysosome. The ATG12–5–16L1 complex is responsible for conjugating members of the ubiquitin-like ATG8 protein family to phosphatidylethanolamine in the growing autophagosomal membrane, known as the phagophore. ATG12–5–16L1 is recruited to the phagophore by a subset of the phosphatidylinositol 3-phosphate-binding seven-bladedß -propeller WIPI proteins. We determined the crystal structure of WIPI2d in complex with the WIPI2 interacting region (W2IR) of ATG16L1 comprising residues 207–230 at 1.85 Å resolution. The structure shows that the ATG16L1 W2IR adopts an alpha helical conformation and binds in an electropositive and hydrophobic groove between WIPI2 ß-propeller blades 2 and 3. Mutation of residues at the interface reduces or blocks the recruitment of ATG12–5–16 L1 and the conjugation of the ATG8 protein LC3B to synthetic membranes. Interface mutants show a decrease in starvation-induced autophagy. Comparisons across the four human WIPIs suggest that WIPI1 and 2 belong to a W2IR-binding subclass responsible for localizing ATG12–5–16 L1 and driving ATG8 lipidation, whilst WIPI3 and 4 belong to a second W34IR-binding subclass responsible for localizing ATG2, and so directing lipid supply to the nascent phagophore. The structure provides a framework for understanding the regulatory node connecting two central events in autophagy initiation, the action of the autophagic PI 3-kinase complex on the one hand and ATG8 lipidation on the other.