Intertwining Cell Adhesion, Gene Expression, and Stress
Da Silva, Alejandro (2023-06-01)
Da Silva, Alejandro
Åbo Akademi - Åbo Akademi University
01.06.2023
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The permanent address of the publication is
https://urn.fi/URN:ISBN:978-952-12-4288-5
https://urn.fi/URN:ISBN:978-952-12-4288-5
Abstract
Cells within an organism are constantly exposed to environmental insults that challenge the homeostasis of their proteome by causing protein misfolding. To survive these adverse situations, cells are equipped with a stress-responsive family of transcription factors called heat shock factors (HSFs). Upon exposure to stress, the HSFs are activated and induce the expression of molecular chaperones, known as heat shock proteins, which in turn aid misfolded proteins to regain their native conformation. HSF1 and HSF2 are the most studied members of the HSFs family, and HSF1 has been considered the master regulator of the proteotoxic stress response. However, despite years of HSFs research, several questions remain unanswered, including: Is there an HSF2-dependent gene expression profile associated with proteotoxic stress? Do HSF1 and HSF2 drive distinct transcriptional programs depending on the type of stress? What are the proteins that interact with HSF2?
The first study of this thesis shows that HSF2 is a prominent transcriptional regulator of the cadherin superfamily of adhesion proteins, and impaired cell-cell adhesion predisposes cells to sustained proteotoxic stress. The second study demonstrates that HSF1 and HSF2 are multi-stress-responsive transcription factors, that trigger distinct transcriptional programs depending on the type of stress. The third study characterizes the protein interactome of HSF2 in a tissue-relevant context and establishes TLN1 as the first adhesion-related HSF2 interacting partner. Lastly, the fourth study in this thesis shows that TLN1 is also present in the nucleus where it strongly binds to chromatin, accumulates in the nucleolus, and regulates gene expression.
The first study of this thesis shows that HSF2 is a prominent transcriptional regulator of the cadherin superfamily of adhesion proteins, and impaired cell-cell adhesion predisposes cells to sustained proteotoxic stress. The second study demonstrates that HSF1 and HSF2 are multi-stress-responsive transcription factors, that trigger distinct transcriptional programs depending on the type of stress. The third study characterizes the protein interactome of HSF2 in a tissue-relevant context and establishes TLN1 as the first adhesion-related HSF2 interacting partner. Lastly, the fourth study in this thesis shows that TLN1 is also present in the nucleus where it strongly binds to chromatin, accumulates in the nucleolus, and regulates gene expression.