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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • DNA-Binding Proteins / metabolism*
  • HSP70 Heat-Shock Proteins / metabolism*
  • Heat-Shock Proteins / metabolism*
  • Hot Temperature*
  • Models, Theoretical
  • Phosphorylation
  • Protein Binding
  • Protein Processing, Post-Translational*
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / radiation effects*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • HSF1 protein, S cerevisiae
  • HSP70 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors