REGULATORY MODULATION OF NF-κB ACTIVITY BY HSP90-BINDING IMMUNOPHILINS AND b-CATENIN

IARA S. SANTA CRUZ1 SOL M. CIUCCI, ALEJANDRA G. ERLEJMAN, MARIO D. GALIGNIANA

Congreso; LXVIII REUNIÓN ANUAL DE SAIC; 2023

-Catenin is a ubiquitous client protein of the chaperone Hsp90 that activates the Wnt-dependent transcriptional pathway responsible of cell adhesion, cell development, and a variety of diseases, including cancer. Its aberrant activation leads to the nuclear accumulation of β-catenin promoting the induction of many oncogenes. NF-κB is a transcription factor that plays key roles in inflammation, stress response, tumour growth, and apoptosis. Previously, we reported that two highly homologous Hsp90-binding immunophilins regulate transcriptional activity of NF-κB, where FKBP52 is an activator and FKBP51 is an inhibitor. Therefore, we hypothesised that these Hsp90-binding immunophilins, -catenin, and NF-B may be integrated in a common functional pathway.To evaluate whether a signalling crosstalk exists between -catenin and NF-B pathways, HEK cells expressing an NF-κB-Luc reporter gene, NF-κB, and increasing concentrations of β-catenin were stimulated (or not) with 0.1 ug/ml phorbol-12-myristate-13-acetate for 7 h. Under both conditions, β-catenin showed a strong inhibitory effect on NF-κB activity. As expected, the overexpression of FKBP52 enhanced NF-B biological activity, whereas β-catenin impaired the immunophilin effect. On the other hand, the overexpression of FKBP51 showed inhibitory action on the NF-B activity, and the expression of β-catenin greatly improved that effect in a concentration-dependent manner. Confocal microscopy studies demonstrated that the mere overexpression of the p65 subunit of NF-B showed β-catenin translocated into the nucleus in unstimulated cells. Both factors, p65 and β-catenin, exhibit nuclear colocalization. Moreover, β-catenin coimmunoprecipitated with p65, indicating the existence of complexes. Interestingly, increased levels of p65 stimulated β-catenin expression. In summary, this study evidences a novel crosstalk between β-catenin and NF-B pathways that is regulated by the Hsp90-binding immunophilins FKBP51 and FKBP52.