Dynamic mitochondrial-nuclear redistribution of the immunophilin FKBP51 is regulated by PKA signalling pathway in the process of adipocyte differentiation

TONEATTO J, CHARó N, GALIGNIANA MD, PIWIEN PILIPUK G

Les Diablerets

Congreso; The 6 th. International Conference on the Hsp90-Chaperone Machine; 2012

Glucocorticoids play an important role in adipogenesis via the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90-Hsp70 and a high molecular weight immunophilin FKBP51 or FKBP52. When 3T3-L1 preadipocytes are induced to differentiate, FKBP51 level progressively increases, FKBP52 decreases, whereas Hsp90, Hsp70, p23 and Cyp40 remain unchanged, as shown by Western blot. Interestingly, when adipogenesis is induced, FKBP51 translocates from mitochondria to the nucleus. FKBP51 is retained in the nucleus upon its interaction with chromatin and the nuclear matrix. FKBP51 nuclear localization is transient, after 48 h it cycles back to mitochondria. Importantly, the dynamic FKBP51 mitochondrial-nuclear shuttling depends on PKA signaling, since its inhibition by PKI or knock down of PKA-cá by siRNA, abrogated FKBP51 nuclear translocation induced by IBMX. In addition, the electrophoretic pattern of migration of FKBP51 is altered by treatment of cells with PKI or knock-down of PKA-cá suggesting that FKBP51 is a PKA substrate. In preadipocytes, FKBP51 co-localizes with PKA-cá in mitochondria. When adipogenesis is triggered PKA also moves to the nucleus co-localizing with FKBP51. Moreover, FKBP51 and GR interaction increases when preadipocytes are induced to differentiate. GR transcriptional capacity is reduced when cells are incubated in the presence of IBMX, forskolin or dibutiryl cAMP, compounds that induced nuclear translocation of FKBP51, but not by an specific activator of EPAC. These findings raise the possibility that the dynamic mitochondrial-nuclear shuttling of FKBP51 regulated by PKA may be key in fine tuning the transcriptional control of GR-target genes required for the acquisition of adipocyte phenotype.