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Feedback regulation of heat shock factor 1 (Hsf1) activity by Hsp70‐mediated trimer unzipping and dissociation from DNA

The EMBO journal, 2020-07, Vol.39 (14), p.e104096-n/a [Peer Reviewed Journal]

2020 The Authors. Published under the terms of the CC BY 4.0 license ;2020 The Authors. Published under the terms of the CC BY 4.0 license. ;2020. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;ISSN: 0261-4189 ;EISSN: 1460-2075 ;DOI: 10.15252/embj.2019104096 ;PMID: 32490574

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Title:
Feedback regulation of heat shock factor 1 (Hsf1) activity by Hsp70‐mediated trimer unzipping and dissociation from DNA
Author: Kmiecik, Szymon W ; Le Breton, Laura ; Mayer, Matthias P
Subjects: Affinity ; Animals ; Attenuation ; Binding sites ; Cell culture ; Cell Line ; Chaperones ; Deoxyribonucleic acid ; DNA ; DNA - chemistry ; DNA - genetics ; DNA - metabolism ; DNA binding ; Domains ; entropic pulling ; Gene deletion ; Heat shock ; Heat shock factors ; heat shock response ; Heat Shock Transcription Factors - chemistry ; Heat Shock Transcription Factors - genetics ; Heat Shock Transcription Factors - metabolism ; HSC70 Heat-Shock Proteins - chemistry ; HSC70 Heat-Shock Proteins - genetics ; HSC70 Heat-Shock Proteins - metabolism ; Hsc70 protein ; HSF1 protein ; HSP40 Heat-Shock Proteins - chemistry ; HSP40 Heat-Shock Proteins - genetics ; HSP40 Heat-Shock Proteins - metabolism ; Hsp70 ; Hsp70 protein ; Humans ; Leucine ; Leucine zipper proteins ; Mice ; Mice, Knockout ; Mutation ; Protein Domains ; Protein Multimerization ; Transcription factors ; Trimers
Is Part Of: The EMBO journal, 2020-07, Vol.39 (14), p.e104096-n/a
Description: The heat shock response is a universal transcriptional response to proteotoxic stress orchestrated by heat shock transcription factor Hsf1 in all eukaryotic cells. Despite over 40 years of intense research, the mechanism of Hsf1 activity regulation remains poorly understood at the molecular level. In metazoa, Hsf1 trimerizes upon heat shock through a leucine‐zipper domain and binds to DNA. How Hsf1 is dislodged from DNA and monomerized remained enigmatic. Here, using purified proteins, we demonstrate that unmodified trimeric Hsf1 is dissociated from DNA in vitro by Hsc70 and DnaJB1. Hsc70 binds to multiple sites in Hsf1 with different affinities. Hsf1 trimers are monomerized by successive cycles of entropic pulling, unzipping the triple leucine‐zipper. Starting this unzipping at several protomers of the Hsf1 trimer results in faster monomerization. This process directly monitors the concentration of Hsc70 and DnaJB1. During heat shock adaptation, Hsc70 first binds to a high‐affinity site in the transactivation domain, leading to partial attenuation of the response, and subsequently, at higher concentrations, Hsc70 removes Hsf1 from DNA to restore the resting state. Synopsis Heat shock transcription factor 1 (Hsf1) is a central regulator of the heat shock response (HSR) in eukaryotic cells. This study demonstrates that the Hsp70 system attenuates the metazoa HSR and restores the resting state, by monomerizing trimeric Hsf1 and thus dissociating it from DNA. Hsp70 chaperones together with J‐domain co‐chaperones dissociate Hsf1 from DNA in vitro. Hsf1 is bound by Hsp70s at distinct sites with different affinities, allowing Hsf1 to closely monitor cellular Hsp70 levels. Starting at the binding site adjacent to the trimerization domain, Hsp70s monomerize Hsf1 trimers by successive cycles of entropic pulling. Mutation or deletion of the identified binding sites potentiate Hsf1 activity in cell culture models. Hsp70 and J‐domain chaperones attenuate the heat shock response in metazoa by monomerizing heat shock transcription factor 1 (Hsf1) and thus removing it from DNA.
Publisher: England: Blackwell Publishing Ltd
Language: English
Identifier: ISSN: 0261-4189
EISSN: 1460-2075
DOI: 10.15252/embj.2019104096
PMID: 32490574
Source: GFMER Free Medical Journals
MEDLINE
PubMed Central
Alma/SFX Local Collection

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Feedback regulation of heat shock factor 1 (Hsf1) activity by Hsp70‐mediated trimer unzipping and dissociation from DNA

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