The role of Heat Shock Protein 90 in the Keap1/Nrf2 Mediated Oxidative-Stress Response

Oxidative and proteotoxic stress are common hallmarks of Neurodegenerative diseases (NDs). Cellular proteostasis is maintained through Heat shock protein (Hsp) 90 and Stress-inducible protein 1 (STIP1) modulating the stability of their substrates (clients). Hsp90/heat shock factor (HSF)1 pathway activation attenuates proteotoxicity. Meanwhile, activating the Kelch-like ECH associated protein 1 (Keap1)/ nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway combats oxidative stress. Numerous studies attempted to individually manipulate the expression of Hsp90 or Nrf2 to treat NDs. Novel interactions of Hsp90 with Nrf2 and Keap1 were discovered via yeast-2-hybrid screening (unpublished data). We analyzed their interactions through NMR spectroscopy, ITC, protein-binding assay, Western blotting, and RT-qPCR. We demonstrated that Hsp90 and STIP1 are modulators of both Nrf2 and Keap1’s protein stability. Keap1 directly binds with STIP1 and Hsp90. Keap1 interacts Hsp90 via the Kelch domain. Our study revealed potential crosstalk between Keap1/Nrf2 and Hsp90/HSF1 cytoprotective pathways and the possibility of co-modulating them