Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation.
Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis. Despite its central role in stress resistance, disease and aging, the mechanisms that control Hsf1 activity remain unresolved. 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. 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. 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. 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.
Whitehead Institute for Biomedical Research, Cambridge, United States.
Xu
X
Zheng
Whitehead Institute for Biomedical Research, Cambridge, United States.
Joanna
J
Krakowiak
Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, United States.
Nikit
N
Patel
Department of Mechanical Engineering, Boston University, Boston, United States.
Ali
A
Beyzavi
Whitehead Institute for Biomedical Research, Cambridge, United States.
Jideofor
J
Ezike
Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, United States.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, United States.
Ahmad S
AS
Khalil
Whitehead Institute for Biomedical Research, Cambridge, United States.
David
0000-0002-9651-6858
D
Pincus
D004268:DNA-Binding Proteins / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006358:Hot Temperature; D008962:Models, Theoretical; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000528:radiation effects*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; C067168:HSF1 protein, S cerevisiae; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors
Hsf1; Hsp70; S. cerevisiae; cell biology; chaperone; computational biology; heat shock; phosphorylation; systems biology; systems modeling