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Influence of Hsp90 and HDAC inhibition and tubulin acetylation on perinuclear protein aggregation in human retinal pigment epithelial cells
Author(s) -
KAARNIRANTA K,
RYHÄNEN T,
VIIRI J,
HYTTINEN J,
UUSITALO H,
SALMINEN A
Publication year - 2010
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2010.2135.x
Subject(s) - hsp90 , geldanamycin , acetylation , microbiology and biotechnology , lactacystin , microtubule , tubulin , proteasome , trichostatin a , chemistry , proteasome inhibitor , heat shock protein , retinal , protein aggregation , organelle , biology , histone deacetylase , biochemistry , histone , gene
Purpose Retinal pigment epithelial (RPE) cells are continually exposed to oxidative stress that contributes to protein misfolding, aggregation and functional abnormalities during aging. The protein aggregates formed at the cell periphery are delivered along the microtubulus network by dynein dependent retrograde trafficking to a juxtanuclear location. Methods Cellular organelles were analysed by transmission electron microscopy of ARPE‐19 cells exposed 5 µM MG‐132, 0.25 µM geldanamycin (GA), 1 µM trichostatin A (TSA), 1 µM taxol (TAX) or 5 µM nocodazole (NOC) for 24 hours. In addition, the cells were treated simultaneously with GA or TSA or TAX or NOC and MG‐132 up to 24 hours. Ubiquitin, Hsp90, Hsp70, acetylated tubulin and Hsc70 protein levels were analyzed by western blotting. Results Hsp90 inhibition by geldanamycin can effectively suppress proteasome inhibitor, MG‐132 –induced protein aggregation in a way that is an independent of HDAC inhibition, or the tubulin acetylation levels in ARPE‐19 cells. However, the tubulin acetylation and polymerization state affects the localization of the proteasome‐inhibitor –induced aggregation. Conclusion Hsp90 inhibition is effectively related to regulation of protein aggregation that is independent of HDAC inhibition or tubulin acetylation levels in the RPE cells. Our findings open new perspectives for understanding the pathogenesis of protein aggregation in retinal cells and can be useful for the development of therapeutic treatments to prevent retinal cell deterioration.