Molecular mechanisms of heat shock factor 1 regulation

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. 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. pathophysiological states caused by the accumulation of α-synuclein aggregates in cells; a hallmark for Parkinsonism. structural protein motif where several alpha helices are coiled together. 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 conformational freedom of the bound polypeptide through steric clashes. Movement of the bound segment away from the membrane or bulky protein mass increases the conformational freedom of the bound polypeptide and thus the entropy of the system. The overall Gibb’s free energy decreases providing the energy for the driving force. a specific sequence in a genome bound by HSFs on stress resulting in the stimulation of heat shock gene transcription. family of proteins/transcription factors that are homolgous to Hsf1 and bind to specific sequences in a genome to modify the gene expression pattern, thereby allowing the organism to respond to a changing environment (heat) or developmental signals. several unrelated, highly conserved families of proteins, the synthesis of which is upregulated on temperature upshift and under other stressful conditions. relatively stable and constant internal conditions allowing the appropriate functioning of all cellular components. set of all proteins present in a cell at any given time. homeostasis of the proteome. stress causing protein misfolding and aggregation that might be toxic to the cell. type of regulation where the end product of a pathway downregulates the pathway. in the biological sense, a molecule that can tune the magnitude of the final outcome of a process or response. transplantation models obtained by injecting a recipient of a specific genetic background with cell lines previously established through the isolation of tumor cells from an animal of the same genetic background. study of the transcriptome, the set of all RNAs produced in a cell at a given time. the system that targets misfolded or unwanted proteins by conjugating lysine sidechains with chains of ubiquitin to the proteasome for degradation. It comprises ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin ligases and the 26S proteasome.