The mitochondrial-nuclear shuttling of the immunophilin FKBP51 is dependent on the activation of HSF1

RUBINO, C.; HANSEN, V.; CIUCCI, S.; ERLEJMAN, A.G; GALIGNIANA, M.D.; MAZAIRA, G.I.

Mar del Plata

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

Sociedad Argentina de Investigación Clínica

In previous works we reported that the immunophilin FKBP51 is a mitochondrial factor that migrates to the nucleus when cells are exposed to oxidative stress. In this work we analyzed the regulation of this phenomenon. Confocal microscopy studies show that the mitochondrial-nuclear shuttling of FKBP51 is accompanied by Hsp70, a chaperone induced under stress conditions and interacts with the TPR domains of the immunophilin. To evaluate whether FKBP51 trafficking occurs with other types of stress, 3T3-L1 cells were exposed to heat-shock (43oC for 30’), UV light (30’), osmotic stress (425 mOsm), hypoxia (250 M DFO), Ca-ATPase inhibition (0.5 μM tapsigargina), metabolic stress (0.5% serum for 16 h), glutathione depletion (0.5 mM BSO for 16 h), etc. FKBP51 always abandons mitochondria and accumulates in the nuclei. The common factor for such heterogeneous stimuli could be the activation of the Heat-Shock Factor-1 (HSF1). To assess whether HSF1 affects FKBP51 trafficking, HSF1-KO MEF cells were exposed to 0.25 mM H2O2 for 1 h. FKBP51 concentrated in the nucleus (and nucleoli) in control wild-type cells only, suggesting that HSF1 is necessary for its FKBP51 trafficking. The mere overexpression of GFP-HSF1 already shows FKBP51 in the nucleus without any stimulation. Accordingly, since cancer cells have high metabolism and production of ROS, we show that the expression of FKBP51 is high, and its location is nuclear. Hence, cell viability was evaluated under normal and oxidative stress conditions (0.25 mM H2O2) by MTT assay in HEK cells overexpressing FKBP51 and/or HSF1. While H2O2 has harmful action on cell proliferation, FKBP51 and/or HSF1 overexpression show protective action. It was confirmed in MEF-KO cells for HSF1, whose growth is reduced, and the inhibitory effect of peroxide is enhanced. It is concluded that FKBP51 and HSF1 cooperate in the cell proliferation mechanism and the resistance to cell death.