TPR-proteins influence the nucleocytoplasmic shuttling of GR

MAZAIRA GI, CIUCCI S, GALIGNIANA MD

Congreso; LXV Reunión Anual de SAIC; 2020

Glucocorticoid receptor (GR) exists as a heterocomplex with the chaperone Hsp90 and a co-chaperone carrying a tetratricopeptide-repeat (TPR) domain through which it interacts with Hsp90. Steroid binding promotes the exchange of TPR proteins on the GR-Hsp90 complex, such that FKBP51 is replaced by its homolog partner FKBP52, an immunophilin that interacts with dynein motors favouring the retrograde transport of GR. In this study, we hypothesized that TPR-domain proteins regulate the subcellular localization of GR. It is shown that GR nuclear accumulation is impaired by overexpression of the recombinant TPR peptide. This disrupts the association between GR-Hsp90 an FKBP52, and consequently, the association with dynein is lost. It also causes loss of association with the importin-β1 adapter transporter (KPNB1), the nuclear pore-associated glycoprotein Nup62 and structures associated with the nuclear matrix. The final GR distribution is the result of the combination of two processes: decreased nuclear import and improved nuclear export. Interestingly, leptomycin B (a CRM1/exportin-1 inhibitor) abolished the effects of TPR peptide overexpression despite not having inhibitory effect itself on the nuclear GR export. These results strongly suggest the existence of a TPR domain-dependent mechanism for nuclear protein export. In summary, our study demonstrates a strong relationship between TPR proteins and the nuclear import mechanism of the receptor, as well as their potential capability to favour the anchorage of the GR to nuclear structures. We propose that the balance of expression of the TPR domain proteins bound to the GR-Hsp90 complex can determine the subcellular localization and the nucleocytoplasmic properties of the receptor and, therefore, its pleiotropic biological properties in different tissues or cell types.