Differential regulation of the glucocorticoid receptor nucleocytoplasmic shuttling by TPR-domain proteins

MAZAIRA GI,; ECHEVERRIA PC,; CIUCCI S,; MONTE M,; GALLO LI; ERLEJMAN A,; GALIGNIANA MD

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

Elsevier

Año: 2021 vol. 1868

0167-4889

A dimer of the heat-shock protein of 90-kDa (Hsp90) represents the critical core of the chaperone complexassociated to the glucocorticoid receptor (GR) oligomer. The C-terminal end of the Hsp90 dimer shapes afunctional acceptor site for co-chaperones carrying tetratricopeptide repeat (TPR) domains, where they bind in amutually exclusive and competitive manner. They impact on the biological properties of the GR?Hsp90 complexand are major players of the GR transport machinery. Recently, we showed that the overexpression of a chimericTPR peptide influences the subcellular distribution of GR. In this study, the functional role of endogenousproteins carrying TPR or TPR-like sequences on GR subcellular distribution was characterized. It is demonstratedthat, contrarily to the positive influence of FKBP52 on GR nuclear accumulation, FKBP51 and 14-3-3 impairedthis property. While SGT1α showed no significant effect, the overexpression of the Ser/Thr phosphatase PP5resulted in a nearly equal nuclear-cytoplasmic redistribution of GR rather than its typical cytoplasmic localizationin the absence of steroid. This observation led to analyse the influence of the phosphorylation status of GR,which resulted not linked to its nucleo-cytoplasmic shuttling mechanism. Nonetheless, it was evidenced that bothPP5 and FKBP52 are related to the anchorage of the GR to nucleoskeleton structures. The influence of these TPRdomain proteins on the steroid-dependent transcriptional activity of GR was also characterized. It is postulatedthat the pleiotropic actions of the GR in different cell types may be the consequence of the relative abundance ofdifferent TPR-domain interacting co-chaperones.