Regulation of heat shock transcription factors and their roles in physiology and disease

Key Points Heat shock transcription factors (HSFs) have broad roles in stress resistance that encompass protection from protein misfolding, inflammation and environmental insults. Structural biology studies reveal a new model for how HSFs bind to their target DNA sequence, whereby the DNA-binding domain of HSFs is exposed to the solvent. In this model, the different HSF isoforms would expose biochemically distinct surfaces, which can be subjected to differential regulation by protein–protein interactions and post-translational modifications to modulate abundance and activity of HSFs. Accordingly, HSFs activate and repress genes that modulate metabolism, survival and proliferation in a context-dependent manner. HSF1 stability and function are compromised in neurodegenerative diseases caused by protein misfolding, and this dysfunction contributes to disease progression. Signalling pathways in cancer cells and tumour stroma activate HSF1 through mechanisms distinct from protein misfolding stress. Heat shock transcription factors (HSFs) regulate heat shock proteins in conditions of thermal stress, but they also control gene expression in other stress conditions, as well as in other contexts, including the regulation of cell proliferation and energy metabolism. HSFs are misregulated in various diseases, such as cancer and neurodegeneration, which underlines their important physiological roles. The heat shock transcription factors (HSFs) were discovered over 30 years ago as direct transcriptional activators of genes regulated by thermal stress, encoding heat shock proteins. The accepted paradigm posited that HSFs exclusively activate the expression of protein chaperones in response to conditions that cause protein misfolding by recognizing a simple promoter binding site referred to as a heat shock element. However, we now realize that the mammalian family of HSFs comprises proteins that independently or in concert drive combinatorial gene regulation events that activate or repress transcription in different contexts. Advances in our understanding of HSF structure, post-translational modifications and the breadth of HSF-regulated target genes have revealed exciting new mechanisms that modulate HSFs and shed new light on their roles in physiology and pathology. For example, the ability of HSF1 to protect cells from proteotoxicity and cell death is impaired in neurodegenerative diseases but can be exploited by cancer cells to support their growth, survival and meta