Hsf1 on a leash – controlling the heat shock response by chaperone titration

https://doi.org/10.1016/j.yexcr.2020.112246Get rights and content
Under a Creative Commons license
open access

Abstract

Heat shock factor 1 (Hsf1) is an ancient transcription factor that monitors protein homeostasis (proteostasis) and counteracts disturbances by triggering a transcriptional programme known as the heat shock response (HSR). The HSR is transiently activated and upregulates the expression of core proteostasis genes, including chaperones. Dysregulation of Hsf1 and its target genes are associated with disease; cancer cells rely on a constitutively active Hsf1 to promote rapid growth and malignancy, whereas Hsf1 hypoactivation in neurodegenerative disorders results in formation of toxic aggregates. These central but opposing roles highlight the importance of understanding the underlying molecular mechanisms that control Hsf1 activity. According to current understanding, Hsf1 is maintained latent by chaperone interactions but proteostasis perturbations titrate chaperone availability as a result of chaperone sequestration by misfolded proteins. Liberated and activated Hsf1 triggers a negative feedback loop by inducing the expression of key chaperones. Until recently, Hsp90 has been highlighted as the central negative regulator of Hsf1 activity. In this review, we focus on recent advances regarding how the Hsp70 chaperone controls Hsf1 activity and in addition summarise several additional layers of activity control.

Keywords

Heat shock factor 1
Hsp70
Hsp90
Protein homeostasis
Misfolded proteins
Heat shock response

Abbreviations

CE2
control element 2
CTA
C-terminal transactivation domain
DBD
DNA-binding domain
ER
endoplasmic reticulum
HSE
heat shock element
Hsf1
heat shock factor 1
Hsp
heat shock protein
HSR
heat shock response
JDP
J-domain protein
LZ
leucine zipper domain
NBD
nucleotide-binding domain
NEF
nucleotide-exchange factor
NTA
N-terminal transactivation domain
PTMs
post-translational modifications
proteostasis
(protein homeostasis)
RD
regulatory domain
SBD
substrate-binding domain
TPR
tetratricopeptide repeat
UPR
unfolded protein response

Cited by (0)