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DAF-21/Hsp90 is required for C. elegans longevity by ensuring DAF-16/FOXO isoform A function.
Milán Somogyvári1, Eszter Gecse1, Csaba Sőti2
1Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.
Scientific Reports
|August 15, 2018
Summary
The heat shock protein DAF-21/Hsp90 regulates longevity by controlling the nuclear entry of the DAF-16A FOXO transcription factor. This chaperone is crucial for lifespan extension, particularly for the DAF-16A isoform.
Area of Science:
- Molecular Biology
- Genetics
- Aging Research
Background:
- The FOXO transcription factor family, including DAF-16 in C. elegans, is a key regulator of longevity and downstream of insulin/IGF signaling.
- DAF-16A and D/F isoforms extend lifespan in daf-2 mutants, highlighting their role in aging pathways.
Purpose of the Study:
- To investigate the role of the DAF-21/Hsp90 chaperone in regulating longevity and its interaction with the DAF-16 FOXO transcription factor.
- To determine if DAF-21 influences DAF-16 localization, transcriptional activity, and lifespan extension in a isoform-specific manner.
Main Methods:
- RNA interference (RNAi) to reduce DAF-21 capacity in wild-type and daf-2 mutant Caenorhabditis elegans.
- Loss-of-function mutations in daf-16 to assess its interaction with daf-21 silencing.
- Analysis of DAF-16A and DAF-16D/F nuclear translocation, mRNA induction, and transcriptional function.
- Assessment of lifespan in transgenic daf-2 mutant strains expressing specific DAF-16 isoforms.
Main Results:
- Reducing DAF-21 capacity shortens lifespan in wild-type worms and decreases the longevity of daf-2 mutants.
- daf-16 loss-of-function mitigates the lifespan-shortening effects of daf-21 silencing.
- DAF-21 specifically promotes DAF-16A nuclear translocation and the induction of DAF-16A-specific mRNAs, but not DAF-16D/F.
- DAF-21 regulates DAF-16A activation upstream of its cellular traffic and is selectively required for DAF-16A-mediated lifespan extension.
Conclusions:
- DAF-21/Hsp90 acts as a critical longevity regulator, influencing lifespan through isoform-specific control of DAF-16 activity.
- Findings reveal spatiotemporal roles for DAF-21 in development and longevity, and uncover an isoform-specific mechanism of DAF-16 regulation.
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