Computational modeling of the eukaryotic heat shock response
Academy of Finland, 2008-2010.
In cooperation with the Software Construction laboratory of TUCS (Academy Professor Ralph Back) and Turku Centre for Biotechnology (Academy Professor Lea Sistonen and Professor John Eriksson)
Cells exposed to elevated temperature or other stress stimuli respond by increased expression of heat shock proteins (HSPs). The heat shock response and the proteins involved have been highly conserved throughout evolution from Escherichia coli to human. In addition to heat, a wide variety of biological (infection, inflammation), physical (radiation, hypoxia) and chemical (alcohols, metals) stressors can induce the response. This is why the heat shock response is also called “stress response” and the heat shock proteins, in consequence, “stress proteins”.
The major HSPs are molecular chaperones with an essential role in directing protein folding and assembly of polypeptides within the cell. Under increased temperatures, the proportion of misfolded proteins (MFPs) suddenly increases and the cell reacts by synthesizing HSPs to assist those proteins in refolding. The stress response is controlled primarily at the transcription level (DNA is transcribed into RNA) by a heat shock factor (HSF). In unstressed cells, HSF is present in the cytoplasm and the nucleus in a monomeric form that has no DNA binding activity through its interactions with HSPs. In response to stress, the monomeric HSFs combine into trimers and accumulate within the nucleus. The response is very rapid, starting within minutes of the temperature rise. In the nucleus, the trimers bind to the heat shock elements (HSE), that is, specific DNA sequences in the heat shock gene promoters. When attached to DNA, HSF becomes phosphorylated. Phosphorylation is a process in which the chemical structure of a protein may be slightly altered, yet possibly leading to major changes in its three-dimensional fold and its function. The transcriptional activation of the heat shock genes leads to elevated levels of HSPs and to the formation of HSF-HSP complexes. Finally, once the stress is discontinued, the trimeric forms of HSF dissociate from the DNA and are converted back into non-active monomers, resulting in resumption of normal synthetic activities. The stress-dependent conversion of HSF into its active form implies that HSF is negatively regulated. The HSPs themselves may regulate the heat shock gene expression via an autoregulatory loop. According to this hypothesis, the increased concentrations of misfolded proteins formed during stress bind specific HSPs, resulting in the activation of HSF.
The sequence of events described above would generate accumulation of large amounts of HSPs, if the stress does not cease for a longer time. This effect would be detrimental to the cell, since HSPs are expensive in terms of energy consumption. Therefore, in such cases, the cell slows the HSP-synthesis as follows: HSPs (e.g., Hsp70, HSBP1) bind to HSFs, thus effectively inactivating the HSFs and making them unable to start the production of more HSPs. A model of the heat shock response can be seen in the figure below.
Figure1: The Heat Shock Response Model.
Physical or chemical stress induces production of unfolded or misfolded proteins. Heat shock factor (HSF) monomers in the cytoplasm form trimers, are phosphorylated, and translocate into the nucleus. HSF trimers bind to heat shock protein gene promoter regions (HSE), leading to induction of HSP gene transcription. Hsp70 gene transcription is down-regulated by interaction of Hsp70 or HSBP1 with the HSF trimers.
- Experimental data (2006) by Claire Hyder, Turku Center for Biotechnolgy, Finland
- We have developed Heat Shock Response Simulator. Please, find it here.
- We are running seminar series on heat shock response. Please find details here.
- We have developed a Bionetgen implementation of the heat shock response.
- We have developed a Petri Net implementation of the heat shock response.
- We have developed a Prism implementation of the heat shock response.
- Refined heat shock response guarded command model
- A. Graham Pockley. “Heat shock proteins as regulators of the immune response”. The Lancet. Published online April 29, 2003. http://image.thelancet.com/extras/02art9148web.pdf