The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regula...

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Autores principales:	Antunica-Noguerol, M., Budziñski, M.L., Druker, J., Gassen, N.C., Sokn, M.C., Senin, S., Aprile-Garcia, F., Holsboer, F., Rein, T., Liberman, A.C., Arzt, E.
Formato:	JOUR
Materias:	fk 506 binding protein fk 506 binding protein 51 glucocorticoid receptor lysine SUMO protein unclassified drug heat shock protein 90 PIAS4 protein, human poly ADP ribose binding protein protein inhibitor of activated STAT animal experiment Article controlled study drug conjugation environmental stress gene expression heat shock hormone binding mouse nerve cell differentiation nerve fiber growth nonhuman priority journal protein processing regulatory mechanism sumoylation animal Bagg albino mouse biological model genetic transcription heat shock response HEK293 cell line human metabolism Animals Heat-Shock Response HEK293 Cells HSP90 Heat-Shock Proteins Humans Lysine Mice, Inbred BALB C Models, Biological Poly-ADP-Ribose Binding Proteins Protein Inhibitors of Activated STAT Receptors, Glucocorticoid Sumoylation Tacrolimus Binding Proteins Transcription, Genetic
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_13509047_v23_n10_p1579_AntunicaNoguerol
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	todo:paper_13509047_v23_n10_p1579_AntunicaNoguerol2023-10-03T16:10:04Z The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51 Antunica-Noguerol, M. Budziñski, M.L. Druker, J. Gassen, N.C. Sokn, M.C. Senin, S. Aprile-Garcia, F. Holsboer, F. Rein, T. Liberman, A.C. Arzt, E. fk 506 binding protein fk 506 binding protein 51 glucocorticoid receptor lysine SUMO protein unclassified drug fk 506 binding protein glucocorticoid receptor heat shock protein 90 PIAS4 protein, human poly ADP ribose binding protein protein inhibitor of activated STAT animal experiment Article controlled study drug conjugation environmental stress gene expression heat shock hormone binding mouse nerve cell differentiation nerve fiber growth nonhuman priority journal protein processing regulatory mechanism sumoylation animal Bagg albino mouse biological model genetic transcription heat shock response HEK293 cell line human metabolism sumoylation Animals Heat-Shock Response HEK293 Cells HSP90 Heat-Shock Proteins Humans Lysine Mice, Inbred BALB C Models, Biological Poly-ADP-Ribose Binding Proteins Protein Inhibitors of Activated STAT Receptors, Glucocorticoid Sumoylation Tacrolimus Binding Proteins Transcription, Genetic FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells. Importantly, impairment of SUMO conjugation to FKBP51 impacts on GR-dependent neuronal signaling and differentiation. We demonstrate that SUMO conjugation to FKBP51 is enhanced by the E3 ligase PIAS4 and by environmental stresses such as heat shock, which impact on GR-dependent transcription. SUMO conjugation to FKBP51 regulates GR hormone-binding affinity and nuclear translocation by promoting FKBP51 interaction within the GR complex. SUMOylation-deficient FKBP51 fails to interact with Hsp90 and GR thus facilitating the recruitment of the closely related protein, FKBP52, which enhances GR transcriptional activity. Moreover, we show that the modification of FKBP51 with SUMO modulates its binding to Hsp90. Our data establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR signaling in a neuronal context. Fil:Druker, J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Liberman, A.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_13509047_v23_n10_p1579_AntunicaNoguerol
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	fk 506 binding protein fk 506 binding protein 51 glucocorticoid receptor lysine SUMO protein unclassified drug fk 506 binding protein glucocorticoid receptor heat shock protein 90 PIAS4 protein, human poly ADP ribose binding protein protein inhibitor of activated STAT animal experiment Article controlled study drug conjugation environmental stress gene expression heat shock hormone binding mouse nerve cell differentiation nerve fiber growth nonhuman priority journal protein processing regulatory mechanism sumoylation animal Bagg albino mouse biological model genetic transcription heat shock response HEK293 cell line human metabolism sumoylation Animals Heat-Shock Response HEK293 Cells HSP90 Heat-Shock Proteins Humans Lysine Mice, Inbred BALB C Models, Biological Poly-ADP-Ribose Binding Proteins Protein Inhibitors of Activated STAT Receptors, Glucocorticoid Sumoylation Tacrolimus Binding Proteins Transcription, Genetic
spellingShingle	fk 506 binding protein fk 506 binding protein 51 glucocorticoid receptor lysine SUMO protein unclassified drug fk 506 binding protein glucocorticoid receptor heat shock protein 90 PIAS4 protein, human poly ADP ribose binding protein protein inhibitor of activated STAT animal experiment Article controlled study drug conjugation environmental stress gene expression heat shock hormone binding mouse nerve cell differentiation nerve fiber growth nonhuman priority journal protein processing regulatory mechanism sumoylation animal Bagg albino mouse biological model genetic transcription heat shock response HEK293 cell line human metabolism sumoylation Animals Heat-Shock Response HEK293 Cells HSP90 Heat-Shock Proteins Humans Lysine Mice, Inbred BALB C Models, Biological Poly-ADP-Ribose Binding Proteins Protein Inhibitors of Activated STAT Receptors, Glucocorticoid Sumoylation Tacrolimus Binding Proteins Transcription, Genetic Antunica-Noguerol, M. Budziñski, M.L. Druker, J. Gassen, N.C. Sokn, M.C. Senin, S. Aprile-Garcia, F. Holsboer, F. Rein, T. Liberman, A.C. Arzt, E. The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51
topic_facet	fk 506 binding protein fk 506 binding protein 51 glucocorticoid receptor lysine SUMO protein unclassified drug fk 506 binding protein glucocorticoid receptor heat shock protein 90 PIAS4 protein, human poly ADP ribose binding protein protein inhibitor of activated STAT animal experiment Article controlled study drug conjugation environmental stress gene expression heat shock hormone binding mouse nerve cell differentiation nerve fiber growth nonhuman priority journal protein processing regulatory mechanism sumoylation animal Bagg albino mouse biological model genetic transcription heat shock response HEK293 cell line human metabolism sumoylation Animals Heat-Shock Response HEK293 Cells HSP90 Heat-Shock Proteins Humans Lysine Mice, Inbred BALB C Models, Biological Poly-ADP-Ribose Binding Proteins Protein Inhibitors of Activated STAT Receptors, Glucocorticoid Sumoylation Tacrolimus Binding Proteins Transcription, Genetic
description	FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells. Importantly, impairment of SUMO conjugation to FKBP51 impacts on GR-dependent neuronal signaling and differentiation. We demonstrate that SUMO conjugation to FKBP51 is enhanced by the E3 ligase PIAS4 and by environmental stresses such as heat shock, which impact on GR-dependent transcription. SUMO conjugation to FKBP51 regulates GR hormone-binding affinity and nuclear translocation by promoting FKBP51 interaction within the GR complex. SUMOylation-deficient FKBP51 fails to interact with Hsp90 and GR thus facilitating the recruitment of the closely related protein, FKBP52, which enhances GR transcriptional activity. Moreover, we show that the modification of FKBP51 with SUMO modulates its binding to Hsp90. Our data establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR signaling in a neuronal context.
format	JOUR
author	Antunica-Noguerol, M. Budziñski, M.L. Druker, J. Gassen, N.C. Sokn, M.C. Senin, S. Aprile-Garcia, F. Holsboer, F. Rein, T. Liberman, A.C. Arzt, E.
author_facet	Antunica-Noguerol, M. Budziñski, M.L. Druker, J. Gassen, N.C. Sokn, M.C. Senin, S. Aprile-Garcia, F. Holsboer, F. Rein, T. Liberman, A.C. Arzt, E.
author_sort	Antunica-Noguerol, M.
title	The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51
title_short	The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51
title_full	The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51
title_fullStr	The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51
title_full_unstemmed	The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51
title_sort	activity of the glucocorticoid receptor is regulated by sumo conjugation to fkbp51
url	http://hdl.handle.net/20.500.12110/paper_13509047_v23_n10_p1579_AntunicaNoguerol
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The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

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