PKA dependent mitochondrial -nuclear redistribution of FKBP51 is required for the control of gene expression during the process of adipogenesis

JUDITH TONEATTO; MARIO D. GALIGNIANA; GRACIELA PIWIEN PILIPUK

Halle Salle

Simposio; International Symposium on Cyclophilins and other Foldases: Cell Signaling Catalysts and Drug Targets; 2013

Obesity, one of the most prevalent health problems worldwide, is the resultant of hypertrophy and hyperplasia of the adipose tissue accompanied by deregulated secretion of adipokines. This makes obesity a major risk factor for chronic diseases such as type II diabetes, cardiovascular disease, and even cancer. Glucocorticoids regulate adipogenesis as well as distribution of adipose tissue; therefore it is relevant to study their action at the molecular level. They act 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 differentiate, FKBP51 expression progressively increases, FKBP52 decreases, and Hsp90, Hsp70, and Cyp40 remain unchanged. Interestingly, FKBP51 rapidly translocates from mitochondria to the nucleus where it is retained upon its interaction with chromatin and the nucleoskeleton. 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. Further, FKBP51 electrophoretic pattern of migration is altered when PKA-c alpha is knock-down 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, coinciding with the reorganization of this nuclear compartment. 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 a specific activator of EPAC. FKBP51 knock-down facilitates while FKBP51 ectopic expression blocks adipogenesis. In summary, the dynamic mitochondrial-nuclear shuttling of FKBP51 regulated by PKA may be key in the reorganization of the nuclear lamina and the control of GR-dependent gene expression required for the acquisition of the adipocyte phenotype.