The regulatory action of HSP90-bindig immunophilins on NF-kB biological activity is impaired beta-catenin

CIUCCI, S. M.; ERLEJMAN, A.G.; MAZAIRA, G.I.; GALIGNIANA, M.D.

Mar del Plata

Congreso; LXVII Reunión anual de la Sociedad Argentina de Investigación Clínica(SAIC); 2022

Sociedad Argentina de Investigación Clínica

Immunophilins (IMMs) belong to a subfamily of chaperones that show rotamase activity. Two of the best characterized IMMs, FKBP51 and FKBP52, were first described in the steroid receptor-Hsp90 complex. Recently we showed that they regulate the biological activity of NF-κB, a factor that plays a dual role in apoptosis since it is required for p53-dependent cell death but impairs TNF-induced apoptosis. In turn, β-catenin is a protein originally related to the E-cadherin cell-cell adhesion system, but it is also a key canonical factor of the Wnt signalling cascade. Importantly, aberrant expression of β-catenin induces malignant transformation of normal cells, and its abnormal activity has been reported in many cancer types. Since β-catenin is an Hsp90-client protein and both IMMs bind to Hsp90, we hypothesized a potential functional involvement of β-catenin and the IMMs in the regulation of NF-κB biological activity. The respective inhibitory and stimulatory action of FKBP51 and FKBP52 on NF-κB transcriptional activity is evidenced here in HEK cells stimulated with PMA. Importantly, this treatment as well as that with TNFa, recruits FKBP52 to the NF-kB. Thereafter, cells overexpressing increasing amounts of β-catenin and stimulated with PMA show that both, the basal activity of NF-κB and the stimulatory action of FKBP52, are supressed in a β-catenin concentration-dependent fashion. Similarly, β-catenin enhances the inhibitory effect of FKBP51 on NF-κB response. To test the eventual functional competition of β-catenin and FKBP52, HEK cells were transfected with constant amounts of β-catenin and increasing amounts of FKBP52. As a result, the IMM reverses the inhibitory action of β-catenin. It is concluded that β-catenin abrogates mthe regulatory actions of both IMMs on NF-κB. Inasmuch as β-catenin is constitutively active in most cancer cells, these findings may justify the limited response seen for NF-kB in these cells, even though FKBP52 is highly expressed.