Nucleocytoplasmic shuttling of the glucocorticoid receptor is influenced by tetratricopeptide repeat-containing proteins

Abstract

It has been demonstrated that tetratricopeptide repeats (TPR)-domain proteins regulate the subcellular localization of the glucocorticoid receptor (GR). This study analyses the influence of the TPR-domain of high molecular weight immunophilins in the retrograde transport mechanism and the nuclear retention of GR. The overexpression of the TPR peptide prevents the efficient nuclear accumulation of the GR by interfering the formation of complexes with the dynein-associated immunophilin FKBP52, the adaptor transporter importin-β1, the nuclear pore-associated glycoprotein Nup62, and nuclear matrix-associated structures. It is also demonstrated that the nuclear import of GR is impaired whereas the GR nuclear export is favoured. Interestingly, the exportin1/CRM1 inhibitor leptomycin-B abolishes the action of TPR peptide overexpression, although the drug cannot inhibit the GR nuclear export itself. This indicates the existence of a TPR-domain-dependent mechanism for the export of nuclear proteins. The findings of this study suggest that the expression balance of those TPR-domain proteins bound to the GR•Hsp90 complex may determine the subcellular localization and nucleocytoplasmic properties of the receptor, and thereby its pleiotropic biological properties in different tissues or cell types.