In addition to maintaining proteostasis at the cellular level, Hsf1 plays important roles in organismal health and disease. The small size of the Hsf1 regulon belies its outsize importance in cellular viability. Indeed, both mammalian and yeast Hsf1 drive a compact set of genes dedicated to proteostasis that forms a densely connected network centered around Hsp70, Hsp40 and Hsp90 ( Mahat et al., 2016 Solís et al., 2016). The depth of functional conservation is underscored by the observation that an active form of human Hsf1 can carry out the essential function of Hsf1 in yeast ( Liu et al., 1997).

DNA interactions known, having been maintained since the last common ancestor of the eukaryotic lineage ( Wu, 1995).

Hsf1 and its cognate DNA binding site, the heat shock element (HSE), represent one of the most conserved protein In eukaryotes, the master transcriptional regulator of the heat shock response is heat shock factor 1 (Hsf1) ( Anckar and Sistonen, 2011).

Although the heat shock response has been extensively studied, key aspects of the pathway remain a mystery including the mechanisms governing its activation and regulation. Chaperones function to maintain protein homeostasis (proteostasis) by enabling de novo protein folding in the crowded intracellular environment and targeting proteins for degradation ( Dobson, 2003 Labbadia and Morimoto, 2015). The heat shock response is an ancient and conserved signaling pathway in cells that regulates the expression of molecular chaperones in the presence of thermal and other environmental stresses ( Lindquist, 1986 Richter et al., 2010). This could be a therapeutic strategy to combat neurodegenerative diseases. Now that we know how Hsf1 is controlled, can we harness this understanding to tune the activity of Hsf1 without disrupting how the chaperones work? If we can activate Hsf1, we can provide cells with more chaperones. In this way, Hsf1 and the chaperones form a feedback loop that ensures that there are always enough chaperones to keep the cell’s proteins folded. When bound to the chaperone, Hsf1 is turned ‘off’ when the chaperone falls off, Hsf1 turns ‘on’ and makes more chaperones when there are enough chaperones, they once again bind to Hsf1 and turn it back ‘off’. The most important finding is that the ‘on/off switch’ that controls Hsf1 is based on whether Hsf1 is itself bound to a chaperone. combined mathematical modelling and experiments in yeast cells. To answer this question, Zheng, Krakowiak et al. A sensor named heat shock factor 1 (Hsf1 for short) increases the amount of chaperones following heat shock. 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. Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis.

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