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Elife. 2016 Nov 10;5. pii: e18638. doi: 10.7554/eLife.18638.

Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation.

Author information

1
Whitehead Institute for Biomedical Research, Cambridge, United States.
2
Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, United States.
3
Department of Mechanical Engineering, Boston University, Boston, United States.
4
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, United States.

Abstract

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.

KEYWORDS:

Hsf1; Hsp70; S. cerevisiae; cell biology; chaperone; computational biology; heat shock; phosphorylation; systems biology; systems modeling

PMID:
27831465
PMCID:
PMC5127643
DOI:
10.7554/eLife.18638
[Indexed for MEDLINE]
Free PMC Article

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