![]() Protein aggregates can be triggered by high temperature in a condition termed “heat shock”. These aggregates are tangles of unfolded proteins that are hallmarks of many neurodegenerative diseases such as Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis (ALS). This leads not only to the cell being unable to work properly, but also to the formation of toxic “aggregates”. In these cases, unfolded proteins can pile up in the cell. However, under some conditions – such as high temperature – proteins are more difficult to fold and the chaperones can become overwhelmed. Cells employ “molecular chaperones” to help proteins to fold properly. Protein folding is critical for life, and cells don’t leave it up to chance. In order to carry out their specific roles inside the cell, the proteins need to “fold” into precise three-dimensional shapes. Proteins are strings of amino acids that carry out crucial activities inside cells, such as harvesting energy and generating the building blocks that cells need to grow. Our work reveals two uncoupled forms of regulation - an ON/OFF chaperone switch and a tunable phosphorylation gain - that allow Hsf1 to flexibly integrate signals from the proteostasis network and cell signaling pathways. Surprisingly, we find that Hsf1 phosphorylation, previously thought to be required for activation, in fact only positively tunes Hsf1 and does so without affecting Hsp70 binding. We develop and experimentally validate a mathematical model of Hsf1 activation by heat shock in which unfolded proteins compete with Hsf1 for binding to Hsp70. Here we show that in budding yeast, Hsf1 basally associates with the chaperone Hsp70 and this association is transiently disrupted by heat shock, providing the first evidence that a chaperone repressor directly regulates Hsf1 activity. Despite its central role in stress resistance, disease and aging, the mechanisms that control Hsf1 activity remain unresolved. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis. These research advances offer new prospects of HSPs as potential targets for therapeutic intervention.Ĭancers heat shock proteins molecular chaperone proteostasis target therapy. In this review, we describe the current understandings about the molecular mechanisms of the major HSP families including HSP90/HSP70/HSP60/HSP110 and small HSPs, how the HSPs keep the protein proteostasis and response to stresses, and we also discuss their roles in diseases and the recent exploration of HSP related therapy and diagnosis to modulate diseases. ![]() Therefore, malfunction of HSPs is related with many diseases, including cancers, neurodegeneration, and other diseases. In addition to their chaperone functions, they also play important roles in cell signaling transduction, cell cycle, and apoptosis regulation. They function as molecular chaperons in cells and work as an integrated network, participating in the folding of newly synthesized polypeptides, refolding metastable proteins, protein complex assembly, dissociating protein aggregate dissociation, and the degradation of misfolded proteins. HSP protein families are classified based on their molecular weights, mainly including large HSPs, HSP90, HSP70, HSP60, HSP40, and small HSPs. The heat shock proteins (HSPs) are ubiquitous and conserved protein families in both prokaryotic and eukaryotic organisms, and they maintain cellular proteostasis and protect cells from stresses.
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