Direct activation of HSF1 by macromolecular crowding and misfolded proteins
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F24%3A00602580" target="_blank" >RIV/61388971:_____/24:00602580 - isvavai.cz</a>
Alternative codes found
RIV/00209805:_____/24:00080015 RIV/00216224:14310/24:00138631
Result on the web
<a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0312524" target="_blank" >https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0312524</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1371/journal.pone.0312524" target="_blank" >10.1371/journal.pone.0312524</a>
Alternative languages
Result language
angličtina
Original language name
Direct activation of HSF1 by macromolecular crowding and misfolded proteins
Original language description
Stress responses play a vital role in cellular survival against environmental challenges, often exploited by cancer cells to proliferate, counteract genomic instability, and resist therapeutic stress. Heat shock factor protein 1 (HSF1), a central transcription factor in stress response pathways, exhibits markedly elevated activity in cancer. Despite extensive research into the transcriptional role of HSF1, the mechanisms underlying its activation remain elusive. Upon exposure to conditions that induce protein damage, monomeric HSF1 undergoes rapid conformational changes and assembles into trimers, a key step for DNA binding and transactivation of target genes. This study investigates the role of HSF1 as a sensor of proteotoxic stress conditions. Our findings reveal that purified HSF1 maintains a stable monomeric conformation independent of molecular chaperones in vitro. Moreover, while it is known that heat stress triggers HSF1 trimerization, a notable increase in trimerization and DNA binding was observed in the presence of protein-based crowders. Conditions inducing protein misfolding and increased protein crowding in cells directly trigger HSF1 trimerization. In contrast, proteosynthesis inhibition, by reducing denatured proteins in the cell, prevents HSF1 activation. Surprisingly, HSF1 remains activated under proteotoxic stress conditions even when bound to Hsp70 and Hsp90. This finding suggests that the negative feedback regulation between HSF1 and chaperones is not directly driven by their interaction but is realized indirectly through chaperone-mediated restoration of cytoplasmic proteostasis. In summary, our study suggests that HSF1 serves as a molecular crowding sensor, trimerizing to initiate protective responses that enhance chaperone activities to restore homeostasis.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10606 - Microbiology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
PLoS ONE
ISSN
1932-6203
e-ISSN
1932-6203
Volume of the periodical
19
Issue of the periodical within the volume
11
Country of publishing house
US - UNITED STATES
Number of pages
23
Pages from-to
e0312524
UT code for WoS article
001358284200035
EID of the result in the Scopus database
2-s2.0-85208408975