J Biol Chem. 2015 Nov 6;290(45):27393-402.

Disruption of Heat Shock Protein 90 (Hsp90)-Protein Kinase Cδ (PKCδ) Interaction by (-)-Maackiain Suppresses Histamine H1 Receptor Gene Transcription in HeLa Cells.

Nariai Y1, Mizuguchi H2, Ogasawara T1, Nagai H1, Sasaki Y1, Okamoto Y1, Yoshimura Y3, Kitamura Y4, Nemoto H5, Takeda N4, Fukui H6.
  • 1From the Departments of Molecular Pharmacology.
  • 2From the Departments of Molecular Pharmacology, guchi003@tokushima-u.ac.jp.
  • 3Clinical Pharmacy.
  • 4Otolaryngology.
  • 5Pharmaceutical Chemistry, and.
  • 6Molecular Studies for Incurable Diseases, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8505, Japan.

 

Abstract

The histamine H1 receptor (H1R) gene is an allergic disease sensitive gene, and its expression level is strongly correlated with the severity of allergic symptoms. (-)-Maackiain was identified as a Kujin-derived anti-allergic compound that suppresses the up-regulation of the H1R gene. However, the underlying mechanism of H1R gene suppression remains unknown. Here, we sought to identify a target protein of (-)-maackiain and investigate its mechanism of action. A fluorescence quenching assay and immunoblot analysis identified heat shock protein 90 (Hsp90) as a target protein of (-)-maackiain. A pull-down assay revealed that (-)-maackiain disrupted the interaction of Hsp90 with PKCδ, resulting in the suppression of phorbol 12-myristate 13-acetate (PMA)-induced up-regulation of H1R gene expression in HeLa cells. Additional Hsp90 inhibitors, including 17-(allylamino)-17-demethoxygeldanamycin, celastrol, and novobiocin also suppressed PMA-induced H1R gene up-regulation. 17-(Allylamino)-17-demethoxygeldanamycin inhibited PKCδ translocation to the Golgi and phosphorylation of Tyr(311) on PKCδ. These data suggest that (-)-maackiain is a novel Hsp90 pathway inhibitor. The underlying mechanism of the suppression of PMA-induced up-regulation of H1R gene expression by (-)-maackiain and Hsp90 inhibitors is the inhibition of PKCδ activation through the disruption of Hsp90-PKCδ interaction. Involvement of Hsp90 in H1R gene up-regulation suggests that suppression of the Hsp90 pathway could be a novel therapeutic strategy for allergic rhinitis.

KEYWORDS: (−)-maackiain; G protein-coupled receptor; PKCdelta; allergic disease-sensitive gene; allergy; gene expression; heat shock protein 90 (Hsp90); histamine; histamine H1 receptor gene; protein-protein interaction

PMID: 26391399

 

HM FIG1

 

 

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