Hsp90 acetylation regulates mineralocorticoid receptor subcellular dynamics and aldosterone‐induced promoter transactivation (1097.15)

Abstract

The mineralocorticoid receptor (MR) is a nuclear receptor that transduces the biological effects of the corticosteroid hormone aldosterone, playing a key role in the regulation of transepithelial Na+ reabsorption, extracellular volume and blood pressure. MR forms cytosolic heterocomplexes with heat‐shock protein 90 (Hsp90), Hsp70 and other proteins such as immunophilins. Interaction with Hsp90 is essential to maintain MR in a ligand‐binding competent conformation and to regulate nucleocytoplasmatic shuttling. Acetylation of residue K295 in Hsp90 regulates its interaction with androgen and glucocorticoid receptors. In this work we hypothesized that Hsp90 acetylation may provide a regulatory step to modulate MR cellular dynamics and activity. We used Hsp90 acetylation mimic mutant K295Q or non‐acetylable mutant K295R to examine MR ligand‐dependent and independent nucleocytoplasmatic shuttling and gene transactivation function in cell models with different endogenous levels of Hsp90 expression. Furthermore, we manipulated endogenous Hsp90 acetylation levels by controlling expression or activity of histone deacetylase 6 (HDAC6), the enzyme responsible for deacetylation of Hsp90‐K295. Taken together, our data demonstrates that Hsp90 expression level and acetylation‐dependent activity are essential for regulating MR subcellular localization, ligand‐induced nuclear translocation and gene transactivation. Grant Funding Source: Supported by grants BFU2010‐16625 and CSD‐2008‐00005 from MINECO, Spain