Influence of Hsp90 and HDAC inhibition and tubulin acetylation on perinuclear protein aggregation in human retinal pigment epithelial cells.
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. We demonstrate that Hsp90 inhibition by geldanamycin can effectively suppress proteasome inhibitor, MG-132-induced protein aggregation in a way that is 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. These 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.
Ryhänen
Tuomas
T
Department of Ophthalmology, University of Eastern Finland, 70211 Kuopio, Finland.
Viiri
Johanna
J
Hyttinen
Juha M T
JM
Uusitalo
Hannu
H
Salminen
Antero
A
Kaarniranta
Kai
K
D000107:Acetylation / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D002457:Cell Extracts; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D010857:Pigment Epithelium of Eye / Q000166:cytology*; D020836:Protein Structure, Quaternary; D014404:Tubulin / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
D016227:Benzoquinones; D002457:Cell Extracts; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047029:Lactams, Macrocyclic; D007976:Leupeptins; D014404:Tubulin; C012589:trichostatin A; D006655:Histone Deacetylases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C001277:geldanamycin