Trends in Biochemical Sciences
ReviewMolecular mechanisms of heat shock factor 1 regulation
Section snippets
It is not only about heat shock
Throughout its lifetime, a cell is often confronted with stressful environmental or intrinsic conditions (Figure 1A) that challenge the homeostasis (see Glossary) and integrity of the cell’s proteome, endangering its survival. To cope with such stressful conditions, a transcriptional program developed early in evolution called the HSR. Following the chance discovery by Ferucci Ritossa [1], the HSR was studied intensely for many years as paradigm of a homeostatic transcriptional program,
Structural insights into Hsf1
Metazoan Hsf1 is a multidomain protein comprising an N-terminal DNA-binding domain (DBD), a trimerization domain of two heptad repeat regions (HR-A and HR-B), a regulatory domain (RD), a third heptad repeat region (HR-C), and a C-terminal transactivation domain (TAD) (Figure 2A, left panel). Hsf1 alternates between monomeric, dimeric, trimeric, and higher-order oligomeric states (discussed in the following section).
Layers of Hsf1 activity regulation
Hsf1-mediated gene expression is rapid and tightly coordinated and organized in multiple levels by complex, highly integrated regulatory mechanisms (Figure 3A). As discussed in the following text, Hsf1 is regulated by a wide variety of different mechanisms: by stress-responsive changes in secondary, tertiary, and quaternary structure; by modulation of its concentration through gene expression and degradation; by localization through regulated nuclear–cytoplasmic shuttling and nuclear
Hsf1: a promising therapeutic target?
Since Hsf1 is a central regulator of the protein quality surveillance circuitry, is it a druggable target? On one side, several cancer entities, including carcinomas of skin, breast, liver, lung, and prostate, as well as lymphomas and leukemias, exploit the antiapoptotic and prosurvival activities of Hsf1 to promote cancer cell survival, progression, and metastasis, increasing the cancer’s malignancy and reducing the survival chances for the patient [75,78., 79., 80., 81., 82.]. Many conditions
Concluding remarks
Although significant progress in understanding of the basic mechanism of Hsf1 regulation at the molecular level has been achieved, many issues remain to be elucidated (see Outstanding questions). The Holy Grail in the field remains the solving of Hsf1 structures in the monomeric and oligomeric states. Intrinsically unstructured regions, which constitute around 50% of the protein [16], make Hsf1 unsuitable for crystallization, and alternative structural methods are required. In addition, the
Acknowledgments
We apologize to all researchers whose work could not be cited and discussed due to space limitations. The members of the Mayer laboratory are acknowledged for helpful discussions and advice. The authors’ work on Hsf1 was funded by the Deutsche Forschungsgemeinschaft (DFG) (German Research Foundation) Project-ID 201348542 – SFB 1036 TP9 and Project-ID 468811147 – MA 1278/11-1.
Declaration of interests
No interests are declared.
Glossary
- α-Synucleopathies
- pathophysiological states caused by the accumulation of α-synuclein aggregates in cells; a hallmark for Parkinsonism.
- Coiled coil
- structural protein motif where several alpha helices are coiled together.
- Entropic pulling
- a mechanism to generate mechanical force by increasing the entropy of a system. The binding of a large molecule like Hsp70 close to a membrane (mitochondrial import) or a bulky protein mass (aggregate or Hsf1 trimerized coiled-coil helices) restricts the
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