Abstract
The molecular chaperone Hsp90 is important for the functional maturation of many client proteins, and inhibitors are in clinical trials for multiple indications in cancer. Hsp90 inhibition activates the heat shock response and can improve viability in a cell model of the P23H misfolding mutation in rhodopsin that causes autosomal dominant retinitis pigmentosa (adRP). Here, we show that a single low dose of the Hsp90 inhibitor HSP990 enhanced visual function and delayed photoreceptor degeneration in a P23H transgenic rat model. This was associated with the induction of heat shock protein expression and reduced rhodopsin aggregation. We then investigated the effect of Hsp90 inhibition on a different type of rod opsin mutant, R135L, which is hyperphosphorylated, binds arrestin and disrupts vesicular traffic. Hsp90 inhibition with 17-AAG reduced the intracellular accumulation of R135L and abolished arrestin binding in cells. Hsf-1−/− cells revealed that the effect of 17-AAG on P23H aggregation was dependent on HSF-1, whereas the effect on R135L was HSF-1 independent. Instead, the effect on R135L was mediated by a requirement of Hsp90 for rhodopsin kinase (GRK1) maturation and function. Importantly, Hsp90 inhibition restored R135L rod opsin localization to wild-type (WT) phenotype in vivo in rat retina. Prolonged Hsp90 inhibition with HSP990 in vivo led to a posttranslational reduction in GRK1 and phosphodiesterase (PDE6) protein levels, identifying them as Hsp90 clients. These data suggest that Hsp90 represents a potential therapeutic target for different types of rhodopsin adRP through distinct mechanisms, but also indicate that sustained Hsp90 inhibition might adversely affect visual function.
Highlights
Hsp90 is an abundant and highly conserved molecular chaperone that is involved in many cellular processes, including the functional maturation of substrate proteins, which are known as ‘clients’ [1,2]
We investigated the effect of Hsp90 inhibition on a different type of rod opsin mutant, R135L, which is hyperphosphorylated, binds arrestin and disrupts vesicular traffic
We have previously shown that 17-AAG could protect against P23H rod opsin in cells [12]; 17-AAG does not efficiently cross the blood retinal barrier [17]
Summary
Hsp is an abundant and highly conserved molecular chaperone that is involved in many cellular processes, including the functional maturation of substrate proteins, which are known as ‘clients’ [1,2]. Several of these client proteins are oncogenes, leading to Hsp emerging as an important target in different types of cancer treatment [3]. Inhibition of Hsp function disrupts the chaperone complex with Heat Shock Factor 1 (HSF-1), causing the activation of HSF-1 and induction of heat shock protein expression [5]. Hsp inhibition can elicit a dual effect, the proteasome-mediated degradation of Hsp client proteins and activation of HSF-1, which induces Hsp and other chaperones to protect against protein aggregation and reduce protein toxicity [6,7,8]
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