Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 32, Pages 12191-12202Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.008822
Keywords
Heat shock factor protein 1 (HSF1); heat shock protein (HSP); proteostasis; Saccharomyces cerevisiae; stress response; cell stress; gene regulation; heat shock response; Hsp70; protein chaperone; transcription factor
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Funding
- National Institutes of Health [R01GM127287]
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Protein homeostasis and cellular fitness in the presence of proteotoxic stress is promoted by heat shock factor 1 (Hsf1), which controls basal and stress-induced expression of molecular chaperones and other targets. The major heat shock proteins and molecular chaperones Hsp70 and Hsp90, in turn, participate in a negative feedback loop that ensures appropriate coordination of the heat shock response with environmental conditions. Features of this regulatory circuit in the budding yeast Saccharomyces cerevisiae have been recently defined, most notably regarding direct interaction between Hsf1 and the constitutively expressed Hsp70 protein Ssa1. Here, we sought to further examine the Ssa1/Hsf1 regulation. We found that Ssa1 interacts independently with both the previously defined CE2 site in the Hsf1 C-terminal transcriptional activation domain and with an additional site that we identified within the N-terminal activation domain. Consistent with both sites bearing a recognition signature for Hsp70, we demonstrate that Ssa1 contacts Hsf1 via its substrate-binding domain and that abolishing either regulatory site results in loss of Ssa1 interaction. Removing Hsp70 regulation of Hsf1 globally dysregulated Hsf1 transcriptional activity, with synergistic effects on both gene expression and cellular fitness when both sites are disrupted together. Finally, we report that Hsp70 interacts with both transcriptional activation domains of Hsf1 in the related yeast Lachancea kluyveri. Our findings indicate that Hsf1 transcriptional activity is tightly regulated to ensure cellular fitness and that a general and conserved Hsp70-HSF1 feedback loop regulates cellular proteostasis in yeast.
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