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

Abstract

Glucocorticoids play an important role in adipogenesis through the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90•Hsp70 and one high molecular weight immunophilin, either 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, and after 48 hours it cycles back to mitochondria. Importantly, this dynamic FKBP51 mitochondrial-nuclear shuttling depends on PKA signaling, because its inhibition by PKI or knockdown of PKA-cα by siRNA, prevented FKBP51 nuclear translocation induced by IBMX. In addition, the electrophoretic pattern of migration of FKBP51 is altered by treatment of cells with PKI or knockdown of PKA-cα, suggesting that FKBP51 is a PKA substrate. In preadipocytes, FKBP51 colocalizes with PKA-cα in mitochondria. When adipogenesis is triggered, PKA-cα also moves to the nucleus colocalizing 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 dibutyryl-cAMP, compounds that induced FKBP51 nuclear translocation, but not by a specific activator of EPAC. FKBP51 knockdown facilitates adipogenesis, whereas 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.

Enhanced Human Decidual Cell–Expressed FKBP51 May Promote Labor-Related Functional Progesterone Withdrawal

“…20 Then, we assessed FKBP51, FKBP52, PR, and GR expression. Immunoblotting indicated that, as reported in other cell types, 32,33 FKBP51 is present in the nucleus and cytoplasm of cultured DCs and that glucocorticoid pays a dominant role in reciprocally up-regulating FKBP51 and down-regulating GR expression. By comparison with FKBP51, PR expression displayed dominant progestin-mediated down-regulation.…”

Adipogenesis is under surveillance of Hsp90 and the high molecular weight Immunophilin FKBP51

“…38 In regard to adipogenesis, we have recently shown that no change is observed in the protein expression level of Hsp90 during the differentiation of 3T3-L1 preadipocytes. 39 It remains to be explored whether there are differences in the expression of the different Hsp90s during adipogenesis and whether they are deregulated in obesity due to the functional importance of this chaperone in response to cell stress.…”

“…FKBP51 expression progressively increases whereas FKBP52 decreases as adipogenesis proceeds. 39,60 The differences observed between these studies may possibly depend on the development of highly sensitive and specific antibodies now available for the study of these IMMs. Importantly, the changes in level of expression of both IMMs during 3T3-L1 preadipocyte differentiation are in agreement with the high expression of FKBP51 and low levels of FKBP52 in white adipose tissue (J.T.…”

“…74 When 3T3-L1 preadipocytes are induced to differentiate, FKBP51 also rapidly and transiently translocates from mitochondria to the nucleus. 39 Adipogenesis is controlled by many signaling pathways that coordinately modulate the sequential activation of transcription factors required for cells to differentiate. 75 We found that IBMX (3-isobutyl-1-methylxanthine), a phosphodiesterase inhibitor that increases intracellular cAMP, and to a lesser extent DEXA, are responsible for the rapid relocalization of mitochondrial FKBP51 to the nucleus (Fig.…”

The Emerging Role of TPR-Domain Immunophilins in the Mechanism of Action of Steroid Receptors

“…This fact is shown in the model of Figure 2-A. It should be noted that FKBP51 was not recovered, associated to cytoplasmic structures of the NPC, although very recent evidence demonstrated that FKBP51 is able to interact with lamin B in the inner face of the nuclear envelope [94,95].…”