Dynamic mitochondrial-nuclear redistribution of the immunophilin FKBP51 is regulated by the PKA signaling pathway to control gene expression during adipocyte differentiation
Glucocorticoids play an important role in adipogenesis through the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90NHsp70 and one high molecular weight immunophilin, either FKBP51 or FKBP52. When 3T3-L1 preadipocytes are induced to differentiate, FKBP51 expression progressively inc...
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todo:paper_00219533_v126_n23_p5357_Toneatto2023-10-03T14:23:34Z Dynamic mitochondrial-nuclear redistribution of the immunophilin FKBP51 is regulated by the PKA signaling pathway to control gene expression during adipocyte differentiation Toneatto, J. Guber, S. Charó, N.L. Susperreguy, S. Schwartz, J. Galigniana, M.D. Piwien-Pilipuk, G. Adipogenesis FKBP51 Glucocorticoid receptor PKA bucladesine cyclic AMP dependent protein kinase fkbp51 protein forskolin glucocorticoid receptor immunophilin isobutylmethylxanthine lamin B protein kinase a c alpha small interfering RNA unclassified drug adipocyte adipogenesis animal cell article cell differentiation cell nucleus matrix cellular distribution chromatin controlled study electrophoretic mobility enzyme inhibition enzyme substrate gene expression regulation gene silencing human human cell intracellular signaling mitochondrion mouse nonhuman nuclear lamina priority journal proadipocyte protein localization protein protein interaction protein transport transcription regulation Adipogenesis FKBP51 Glucocorticoid receptor PKA 1-Methyl-3-isobutylxanthine 3T3-L1 Cells Adipogenesis Animals Cell Differentiation Cell Nucleus Chromatin Colforsin Cyclic AMP-Dependent Protein Kinases Gene Expression Regulation HSP70 Heat-Shock Proteins HSP90 Heat-Shock Proteins Mice Mitochondria Peptides Protein Binding Protein Kinase C-alpha Protein Kinase Inhibitors Protein Transport Receptors, Glucocorticoid RNA, Small Interfering Signal Transduction Tacrolimus Binding Proteins Glucocorticoids play an important role in adipogenesis through the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90NHsp70 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-ca 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-ca, suggesting that FKBP51 is a PKA substrate. In preadipocytes, FKBP51 colocalizes with PKA-ca in mitochondria. When adipogenesis is triggered, PKA-ca 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 dibutyrylcAMP, 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 © 2013. Published by The Company of Biologists Ltd. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00219533_v126_n23_p5357_Toneatto |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Adipogenesis FKBP51 Glucocorticoid receptor PKA bucladesine cyclic AMP dependent protein kinase fkbp51 protein forskolin glucocorticoid receptor immunophilin isobutylmethylxanthine lamin B protein kinase a c alpha small interfering RNA unclassified drug adipocyte adipogenesis animal cell article cell differentiation cell nucleus matrix cellular distribution chromatin controlled study electrophoretic mobility enzyme inhibition enzyme substrate gene expression regulation gene silencing human human cell intracellular signaling mitochondrion mouse nonhuman nuclear lamina priority journal proadipocyte protein localization protein protein interaction protein transport transcription regulation Adipogenesis FKBP51 Glucocorticoid receptor PKA 1-Methyl-3-isobutylxanthine 3T3-L1 Cells Adipogenesis Animals Cell Differentiation Cell Nucleus Chromatin Colforsin Cyclic AMP-Dependent Protein Kinases Gene Expression Regulation HSP70 Heat-Shock Proteins HSP90 Heat-Shock Proteins Mice Mitochondria Peptides Protein Binding Protein Kinase C-alpha Protein Kinase Inhibitors Protein Transport Receptors, Glucocorticoid RNA, Small Interfering Signal Transduction Tacrolimus Binding Proteins |
| spellingShingle |
Adipogenesis FKBP51 Glucocorticoid receptor PKA bucladesine cyclic AMP dependent protein kinase fkbp51 protein forskolin glucocorticoid receptor immunophilin isobutylmethylxanthine lamin B protein kinase a c alpha small interfering RNA unclassified drug adipocyte adipogenesis animal cell article cell differentiation cell nucleus matrix cellular distribution chromatin controlled study electrophoretic mobility enzyme inhibition enzyme substrate gene expression regulation gene silencing human human cell intracellular signaling mitochondrion mouse nonhuman nuclear lamina priority journal proadipocyte protein localization protein protein interaction protein transport transcription regulation Adipogenesis FKBP51 Glucocorticoid receptor PKA 1-Methyl-3-isobutylxanthine 3T3-L1 Cells Adipogenesis Animals Cell Differentiation Cell Nucleus Chromatin Colforsin Cyclic AMP-Dependent Protein Kinases Gene Expression Regulation HSP70 Heat-Shock Proteins HSP90 Heat-Shock Proteins Mice Mitochondria Peptides Protein Binding Protein Kinase C-alpha Protein Kinase Inhibitors Protein Transport Receptors, Glucocorticoid RNA, Small Interfering Signal Transduction Tacrolimus Binding Proteins Toneatto, J. Guber, S. Charó, N.L. Susperreguy, S. Schwartz, J. Galigniana, M.D. Piwien-Pilipuk, G. Dynamic mitochondrial-nuclear redistribution of the immunophilin FKBP51 is regulated by the PKA signaling pathway to control gene expression during adipocyte differentiation |
| topic_facet |
Adipogenesis FKBP51 Glucocorticoid receptor PKA bucladesine cyclic AMP dependent protein kinase fkbp51 protein forskolin glucocorticoid receptor immunophilin isobutylmethylxanthine lamin B protein kinase a c alpha small interfering RNA unclassified drug adipocyte adipogenesis animal cell article cell differentiation cell nucleus matrix cellular distribution chromatin controlled study electrophoretic mobility enzyme inhibition enzyme substrate gene expression regulation gene silencing human human cell intracellular signaling mitochondrion mouse nonhuman nuclear lamina priority journal proadipocyte protein localization protein protein interaction protein transport transcription regulation Adipogenesis FKBP51 Glucocorticoid receptor PKA 1-Methyl-3-isobutylxanthine 3T3-L1 Cells Adipogenesis Animals Cell Differentiation Cell Nucleus Chromatin Colforsin Cyclic AMP-Dependent Protein Kinases Gene Expression Regulation HSP70 Heat-Shock Proteins HSP90 Heat-Shock Proteins Mice Mitochondria Peptides Protein Binding Protein Kinase C-alpha Protein Kinase Inhibitors Protein Transport Receptors, Glucocorticoid RNA, Small Interfering Signal Transduction Tacrolimus Binding Proteins |
| description |
Glucocorticoids play an important role in adipogenesis through the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90NHsp70 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-ca 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-ca, suggesting that FKBP51 is a PKA substrate. In preadipocytes, FKBP51 colocalizes with PKA-ca in mitochondria. When adipogenesis is triggered, PKA-ca 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 dibutyrylcAMP, 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 © 2013. Published by The Company of Biologists Ltd. |
| format |
JOUR |
| author |
Toneatto, J. Guber, S. Charó, N.L. Susperreguy, S. Schwartz, J. Galigniana, M.D. Piwien-Pilipuk, G. |
| author_facet |
Toneatto, J. Guber, S. Charó, N.L. Susperreguy, S. Schwartz, J. Galigniana, M.D. Piwien-Pilipuk, G. |
| author_sort |
Toneatto, J. |
| title |
Dynamic mitochondrial-nuclear redistribution of the immunophilin FKBP51 is regulated by the PKA signaling pathway to control gene expression during adipocyte differentiation |
| title_short |
Dynamic mitochondrial-nuclear redistribution of the immunophilin FKBP51 is regulated by the PKA signaling pathway to control gene expression during adipocyte differentiation |
| title_full |
Dynamic mitochondrial-nuclear redistribution of the immunophilin FKBP51 is regulated by the PKA signaling pathway to control gene expression during adipocyte differentiation |
| title_fullStr |
Dynamic mitochondrial-nuclear redistribution of the immunophilin FKBP51 is regulated by the PKA signaling pathway to control gene expression during adipocyte differentiation |
| title_full_unstemmed |
Dynamic mitochondrial-nuclear redistribution of the immunophilin FKBP51 is regulated by the PKA signaling pathway to control gene expression during adipocyte differentiation |
| title_sort |
dynamic mitochondrial-nuclear redistribution of the immunophilin fkbp51 is regulated by the pka signaling pathway to control gene expression during adipocyte differentiation |
| url |
http://hdl.handle.net/20.500.12110/paper_00219533_v126_n23_p5357_Toneatto |
| work_keys_str_mv |
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