Person:

Solis, Eric

Despite its eponymous association with proteotoxic stress, heat shock factor 1 (Hsf1 in yeast and HSF1 in mammals) is required for viability of yeast and many human cancer cells, yet its essential role remains undefined. Here we show that rapid nuclear export of Hsf1 achieved in a matter of minutes by a chemical genetics approach results in cell growth arrest in a matter of hours, which was associated with massive protein aggregation and eventual cell death. Genome-wide analyses of immediate gene expression changes induced by Hsf1 nuclear export revealed a basal transcriptional program comprising 18 genes, predominately encoding chaperones and other proteostasis factors. During heat shock, Hsf1 increases the magnitude of its transcriptional program without expanding its breadth. Strikingly, engineered Hsf1-independent co-expression of just Hsp70 and Hsp90 chaperones enabled robust cell growth in the complete absence of Hsf1. A comparative genomic analysis of mammalian fibroblasts and embryonic stem cells revealed that HSF1 lacks a basal transcriptional program but still regulates a similar set of chaperone genes during heat shock. Our work demonstrates that basal chaperone gene expression is a housekeeping mechanism controlled by Hsf1 in yeast and serves as a roadmap for defining the housekeeping function of HSF1 in many cancers. Finally, we investigate the mechanism causing age-associated inactivation of Hsf1 during replicative aging in budding yeast. Using classic and chemical-genetic tools, we demonstrate that inactivation is due to constitutive activation of the distinct General Stress Response. These experiments reveal that stress pathway crosstalk inhibits Hsf1 activation during replicative aging and under physiological stress in young cells.

Despite its eponymous association with the heat shock response, yeast heat shock factor 1 (Hsf1) is essential even at low temperatures. Here we show that engineered nuclear export of Hsf1 results in cytotoxicity associated with massive protein aggregation. Genome-wide analysis revealed that Hsf1 nuclear export immediately decreased basal transcription and mRNA expression of 18 genes, which predominately encode chaperones. Strikingly, rescuing basal expression of Hsp70 and Hsp90 chaperones enabled robust cell growth in the complete absence of Hsf1. With the exception of chaperone gene induction, the vast majority of the heat shock response was Hsf1-independent. By comparative analysis of mammalian cell lines, we found that only heat shock-induced but not basal expression of chaperones is dependent on the mammalian Hsf1 homolog (HSF1). Our work reveals that yeast chaperone gene expression is an essential housekeeping mechanism and provides a roadmap for defining the function of HSF1 as a driver of oncogenesis.