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Unraveling complex interplay between heat shock factor 1 and 2 splicing isoforms
Sylvain Lecomte1, Léa Reverdy, Catherine Le Quément
1Transcription, Environment and Cancer group, Institut de Recherche sur la Santé, l'Environnement et le Travail, Inserm U1085, Université de Rennes 1, Rennes, France.
Plos One
|February 19, 2013
Summary
Heat shock factors (HSF1 and HSF2) regulate cellular responses to proteotoxic stress. Their specific isoforms (α and β) quantitatively control the stress response strength, with HSF1α being more active and HSF2β having a regulatory role.
Area of Science:
- Molecular Biology
- Cellular Stress Response
Background:
- Chaperone synthesis, crucial for managing proteotoxic stress, is regulated by heat shock factors (HSFs).
- HSF1 and HSF2, key HSF family members, form heterotrimers and have α and β splicing isoforms, adding complexity to transcriptional regulation.
- The roles of these HSF splicing isoforms remain under-investigated.
Purpose of the Study:
- To investigate the transcriptional activity of HSF1 and HSF2 splicing isoforms.
- To understand the impact of proteasome inhibition on HSF isoform activity.
- To elucidate the regulatory roles of HSF2 isoforms in the context of HSF1 activity.
Main Methods:
- Transfection of HSF1 and HSF2 isoforms into Hsf1/Hsf2-deleted mouse embryonic fibroblasts (iMEFs).
- Exposure to proteasome inhibitor MG132 to induce proteotoxic stress.
- Mathematical modeling to analyze the regulatory network of HSF isoforms.
Main Results:
- HSF1α demonstrated significantly higher transcriptional activity than HSF1β post-MG132 treatment.
- HSF2 alone showed no transcriptional activity, but HSF2β inhibited HSF1β-dependent transactivation.
- Proteasome inhibition was found to regulate Hsf2 mRNA splicing.
- Cellular balance of HSF isoforms quantitatively dictates the proteotoxic stress response strength.
Conclusions:
- The relative abundance of HSF1 and HSF2 isoforms is a key determinant of the cellular proteotoxic stress response.
- HSF2β plays a crucial regulatory role, modulating HSF1 activity.
- Cellular stress can influence HSF2 splicing, adding another layer of regulatory control.
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