Review
Molecular mechanisms of heat shock factor 1 regulation

https://doi.org/10.1016/j.tibs.2021.10.004Get rights and content

Highlights

  • Hsf1 is a thermosensor itself and directly senses elevated temperatures with conformational changes in the leucin zipper domains HR-A/B and HR-C.

  • Hsp70, not Hsp90 as proposed in many studies, is the main chaperone regulating Hsf1 activity by monomerizing Hsf1 trimers and thereby dissociating Hsf1 from DNA.

  • A complex network of post-translational modifications (PTMs) accompanies Hsf1 through its lifetime, providing fine-tuning of its activity to integrate many input signals and to meet the respective needs of the cell at any time.

  • Hsf1 activity downregulation could be beneficial to treat cancer, whereas Hsf1 upregulation may help to counteract neurodegenerative diseases like Parkinson or Alzheimer, or could be a key to healthy aging by prolonging the optimal proteostasis capacity.

To thrive and to fulfill their functions, cells need to maintain proteome homeostasis even in the face of adverse environmental conditions or radical restructuring of the proteome during differentiation. At the center of the regulation of proteome homeostasis is an ancient transcriptional mechanism, the so-called heat shock response (HSR), orchestrated in all eukaryotic cells by heat shock transcription factor 1 (Hsf1). As Hsf1 is implicated in aging and several pathologies like cancer and neurodegenerative disorders, understanding the regulation of Hsf1 could open novel therapeutic opportunities. In this review, we discuss the regulation of Hsf1’s transcriptional activity by multiple layers of control circuits involving Hsf1 synthesis and degradation, conformational rearrangements and post-translational modifications (PTMs), and molecular chaperones in negative feedback loops.

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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