PXD037662

PXD037662 is an original dataset announced via ProteomeXchange.

Title	Excess protein synthesis, denatured proteins or molecular crowding spontaneously induce HSF1 trimerisation and activation
Description	Stress responses are a key feature of normal physiology and are usurped by cancer cells to ensure enhanced protein synthesis for growth, to compensate for genomic instability, and to protect cancer cells from therapy induced stress. Heat shock factor-1 (HSF1) is a major stress-response transcription factor, and its activity is markedly enhanced in cancer. Stress induces HSF1 conformational changes and post-translational modifications, leading to assembly of active HSF1 trimers that bind DNA to control target gene expression. Although the function of HSF1 in transcription is relatively well-known, the mechanisms leading to HSF1 activation and enhanced stress response in tumours are unclear. To investigate whether HSF1 is a primary sensor of proteotoxic stress in vivo, we studied the range of conditions that can cause HSF1 activation in vitro and in cells, and conditions that prevent its activation. We show that purified recombinant HSF1 adopts a stable monomeric conformation in vitro. Heat stress caused a conformational change and the assembly of HSF1 trimers. Conditions leading to protein denaturation, including heat stress, crowding, Hsp90 inhibition, or proteasome inhibition, all directly lead to HSF1 activation. In contrast, HSF1 activation in vivo is prevented by proteosynthesis inhibition, which reduces the amount of denatured proteins in the cell. These results establish that HSF1 is a direct sensor of proteotoxic stress, independent of post-translational modification, where abrupt environmental changes that cause protein denaturation simultaneously induce a conformational change in monomeric HSF1 leading to its activation. This mechanism explains the universal ability of cells to respond to proteotoxic stress and trigger a protective response when increased chaperone activities are required to restore homeostasis.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:54:59.971.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lenka Hernychova
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2022-10-24 01:07:08	ID requested
1	2024-08-14 07:56:09	announced
⏵ 2	2024-10-22 06:55:00	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: LC-MSMS,HSF1, stress, Hsp70, Hsp90, crowding, HDX-MS, protein folding

MUDr. Petr Muller, Ph.D.
contact affiliation	Recamo, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 656 53 Czech Republic
contact email	muller@mou.cz
lab head
Lenka Hernychova
contact affiliation	Masaryk Memorial Cancer Institutre, Zluty kopec 7, Brno 656 53, Czech Republic
contact email	lenka.hernychova@mou.cz
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/08/PXD037662

PRIDE project URI

• PRIDE
  1. PXD037662
     1. Label: PRIDE project
     2. Name: Excess protein synthesis, denatured proteins or molecular crowding spontaneously induce HSF1 trimerisation and activation