DYNAMIC MITOCHONDRAL-NUCLEAR RESIDSTRIBUTION OF THE IMMUNOPHILIN FKBP51 IS REGULATED BY PKA SIGNALING PATHWAY DURING THE PROCESS OF ADIPOCYTE DIFFERENTIATION.

JUDITH TONEATTO; NANCY CHARÓ; SEBASTIÁN SUSPERREGUY; GRACIELA PIWIEN–PILIPUK

Congreso; South American Spring Symposium in Signal Transduction and Molecular Medicine.; 2012

South American Spring Symposium in Signal Transduction and Molecular Medicine

Glucocorticoids play an important role in adipogenesis via theglucocorticoid receptor (GR) that forms a heterocomplex with Hsp90-Hsp70 and a high molecular weight immunophilin FKBP51 or FKBP52. Wehave found that FKBP51 level of expression progressively increases,FKBP52 decreases, whereas Hsp90, Hsp70, and p23 remain unchangedwhen 3T3-L1 preadipocytes differentiate. Interestingly, FKBP51translocates from mitochondria to the nucleus at the onset ofadipogenesis. FKBP51 nuclear localization is transient, after 48 h it cyclesback to mitochondria. We found that the dynamic FKBP51 mitochondrialnuclearshuttling depends on PKA signaling, since its inhibition bymyristoilated-PKI or knock down of PKA-cα by siRNA, abrogated FKBP51nuclear translocation induced by IBMX. Further, FKBP51electrophoreticpattern of migration is altered by treatment of cells with PKI or knock-downof PKA-cα suggesting that FKBP51 is a PKA substrate. In preadipocytes,FKBP51 co-localizes with PKA-cα in mitochondria. When adipogenesis istriggered, PKA also moves to the nucleus co-localizing with FKBP51.Moreover, FKBP51 and GR interaction increases when preadipocytesdifferentiate. GR transcriptional capacity is reduced when cells areincubated in the presence of IBMX, forskolin or diButiril-cAMP, compoundsthat induced nuclear translocation of FKBP51, but not by 8-(4-chlorophenylthio)-2´O-methyladenosine 3´, 5´cyclic-monophosphate, anactivator of the non-classical c-AMP pathway that does not induceFKBP51 nuclear translocation. These findings show for the first time thatthe dynamic mitochondrial-nuclear shuttling of FKBP51 is regulated byPKA and is key in fine tuning the transcriptional control of GR-target genesrequired for the acquisition of adipocyte phenotype.