Dynamic Mitochondrial-Nuclear Redistribution of the Immunophilin FKBP51 is Regulated by PKA Signaling Pathway in the Process of Adipocyte Differentiation

JUDITH TONEATTO; NANCY L. CHARÓ; MARIO D. GALIGNIANA; GRACIELA PIWIEN PILIPUK

Les Diablerets

Conferencia; The 6th International Conference on the Hsp90 Chaperone Machinery; 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. We have previously shown that FKBP51 level of expression progressively increases, FKBP52 decreases, whereas Hsp90, Hsp70, and p23 remain unchanged when 3T3-L1 preadipocytes differentiate. Interestingly, FKBP51 translocates from mitochondria to the nucleus at the onset of adipogenesis. FKBP51 nuclear localization is transient, after 48 h it cycles back to mitochondria. In the present work, we show that the dynamic FKBP51 mitochondrial-nuclear shuttling depends on PKA signaling, since its inhibition by myristoilated-PKI or knock down of PKA-c?¿ by siRNA, abrogated FKBP51 nuclear translocation induced by IBMX. Further, FKBP51electrophoretic pattern of migration is altered by treatment of cells with PKI or knock-down of PKA-c?¿ suggesting that FKBP51 is a PKA substrate. In preadipocytes, FKBP51 co-localizes with PKA-c?¿ in mitochondria. When adipogenesis is triggered, PKA also moves to the nucleus co-localizing with FKBP51. Moreover, FKBP51 and GR interaction increases when preadipocytes differentiate. GR transcriptional capacity is reduced when cells are incubated in the presence of IBMX, forskolin or diButiril-cAMP, compounds that induced nuclear translocation of FKBP51, but not by 8-(4-chlorophenylthio)-2?LO-methyladenosine 3?L, 5?Lcyclic-monophosphate, an activator of the non-classical c-AMP pathway that does not induce FKBP51 nuclear translocation. These findings show for the first time that the dynamic mitochondrial-nuclear shuttling of FKBP51 is regulated by PKA and may be key in fine tuning the transcriptional control of GR-target genes required for the acquisition of adipocyte phenotype.