Dynamic mitochondrial-nuclear redistribution of the immunophilin FKBP51 is regulated by PKA signaling pathway to control gene expression in the process of adipocyte differentiation

TONEATTO, J. ; SERGIO GUBER; N. CHARO; S. SUSPERREGUY; J. SCHWARTZ; M.D. GALIGNIANA; G. PIWIEN PILIPUK

JOURNAL OF CELL SCIENCE

COMPANY OF BIOLOGISTS LTD

Año: 2013 vol. 126 p. 5357 - 5368

0021-9533

Glucocorticoids play an important role in adipogenesis via the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90?Hsp70 and one high molecular weight immunophilin FKBP51 or FKBP52.  When 3T3-L1 preadipocytes are induced to differentiate, FKBP51 expression progressively increases, whereas FKBP52 decreases, and Hsp90, Hsp70, p23 and Cyp40 remain unchanged.  Interestingly, FKBP51 rapidly translocates from mitochondria to the nucleus where it is retained upon its interaction with chromatin and the nuclear matrix.  FKBP51 nuclear localization is transient, after 48 h it cycles back to mitochondria.  Importantly, this dynamic FKBP51 mitochondrial-nuclear shuttling depends on PKA signaling, since its inhibition by PKI or knock-down of PKA-c alpha by siRNA, abrogated FKBP51 nuclear translocation induced by IBMX.  In addition, FKBP51 electrophoretic pattern of migration is altered by treatment of cells with PKI or knock-down of PKA-c alpha suggesting that FKBP51 is a PKA substrate.  In preadipocytes, FKBP51 co-localizes with PKA-c alpha in mitochondria. When adipogenesis is triggered, PKA-c alpha also moves to the nucleus co-localizing with FKBP51 mainly in the nuclear lamina.  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 FKBP51 nuclear translocation , but not by an specific activator of EPAC.  FKBP51 knock-down facilitates while ectopic expression of FKBP51 blocks adipogenesis. These findings indicate 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.