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Measurements of Physiological Stress Responses in C. Elegans
Published on: May 21, 2020
Hsp90 interaction with INrf2(Keap1) mediates stress-induced Nrf2 activation
Suryakant K Niture1, Anil K Jaiswal
1Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
The Journal of Biological Chemistry
|September 25, 2010
Summary
Heat shock protein 90 (Hsp90) stabilizes INrf2 during stress, promoting Nrf2 activation. This interaction, regulated by phosphorylation, controls cytoprotective protein induction and cancer protection.
Area of Science:
- Molecular Biology
- Cellular Stress Response
Background:
- Nrf2 activation is crucial for cellular defense against oxidative stress and cancer.
- INrf2 (Keap1) typically targets Nrf2 for degradation via the Cul3/Rbx1 complex.
- The precise regulation of Nrf2 activation under stress requires further elucidation.
Purpose of the Study:
- To investigate the novel role of heat shock protein 90 (Hsp90) in regulating INrf2 and Nrf2 activation.
- To elucidate the molecular mechanisms underlying Hsp90's involvement in stress-induced Nrf2 signaling.
Main Methods:
- Co-immunoprecipitation and domain mapping to identify Hsp90-INrf2 interaction sites.
- Western blotting to assess protein levels and phosphorylation.
- Inhibitor studies and site-directed mutagenesis to probe signaling pathways.
Main Results:
- Hsp90 directly interacts with and stabilizes INrf2 during heat shock stress.
- Heat shock and antioxidants induce Hsp90 and CK2-mediated phosphorylation of INrf2 at Thr55.
- This phosphorylation enhances Hsp90-INrf2 interaction, leading to Nrf2 release and activation.
Conclusions:
- Stress-induced Hsp90-INrf2 interaction is a novel regulatory mechanism for Nrf2 activation.
- This pathway controls the induction of cytoprotective proteins, offering potential therapeutic targets for cancer and stress-related diseases.
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