Histone Deacetylase 6-Controlled Hsp90 Acetylation Significantly Alters Mineralocorticoid Receptor Subcellular Dynamics But Not its Transcriptional Activity.
The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily that transduces the biological effects of corticosteroids. Its best-characterized role is to enhance transepithelial sodium reabsorption in response to increased aldosterone levels. In addition, MR participates in other aldosterone- or glucocorticoid-controlled processes such as cardiovascular homeostasis, adipocyte differentiation or neurogenesis, and regulation of neuronal activity in the hippocampus. Like other steroid receptors, MR forms cytosolic heterocomplexes with heat shock protein (Hsp) 90), Hsp70, and other proteins such as immunophilins. Interaction with Hsp90 is thought to maintain MR in a ligand-binding competent conformation and to regulate ligand-dependent and -independent nucleocytoplasmatic shuttling. It has previously been shown that acetylation of residue K295 in Hsp90 regulates its interaction with the androgen receptor and glucocorticoid receptor (GR). In this work we hypothesized that Hsp90 acetylation provides a regulatory step to modulate MR cellular dynamics and activity. We used Hsp90 acetylation mimic mutant K295Q or nonacetylatable mutant K295R to examine whether MR nucleocytoplasmatic shuttling and gene transactivation are affected. Furthermore, we manipulated endogenous Hsp90 acetylation levels by controlling expression or activity of histone deacetylase 6 (HDAC6), the enzyme responsible for deacetylation of Hsp90-K295. Our data demonstrates that HDAC6-mediated Hsp90 acetylation regulates MR cellular dynamics but it does not alter its function. This stands in contrast with the down-regulation of GR by HDAC6, suggesting that Hsp90 acetylation may play a role in balancing relative MR and GR activity when both factors are co-expressed in the same cell.
Department of Physiology (R.J.-C., F.L.-D., T.G., D.A.d.l.R.), Institute of Biomedical Technologies and Center for Biomedical Research of the Canary Islands, University of La Laguna, Tenerife 38071, Spain; and INSERM UMRS 1138 (N.J., N.F.), Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris 75006, France.
Rubén
R
Jiménez-Canino
Department of Physiology (R.J.-C., F.L.-D., T.G., D.A.d.l.R.), Institute of Biomedical Technologies and Center for Biomedical Research of the Canary Islands, University of La Laguna, Tenerife 38071, Spain; and INSERM UMRS 1138 (N.J., N.F.), Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris 75006, France.
Fabián
F
Lorenzo-Díaz
Department of Physiology (R.J.-C., F.L.-D., T.G., D.A.d.l.R.), Institute of Biomedical Technologies and Center for Biomedical Research of the Canary Islands, University of La Laguna, Tenerife 38071, Spain; and INSERM UMRS 1138 (N.J., N.F.), Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris 75006, France.
Frederic
F
Jaisser
Department of Physiology (R.J.-C., F.L.-D., T.G., D.A.d.l.R.), Institute of Biomedical Technologies and Center for Biomedical Research of the Canary Islands, University of La Laguna, Tenerife 38071, Spain; and INSERM UMRS 1138 (N.J., N.F.), Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris 75006, France.
Nicolette
N
Farman
Department of Physiology (R.J.-C., F.L.-D., T.G., D.A.d.l.R.), Institute of Biomedical Technologies and Center for Biomedical Research of the Canary Islands, University of La Laguna, Tenerife 38071, Spain; and INSERM UMRS 1138 (N.J., N.F.), Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris 75006, France.
Teresa
T
Giraldez
Department of Physiology (R.J.-C., F.L.-D., T.G., D.A.d.l.R.), Institute of Biomedical Technologies and Center for Biomedical Research of the Canary Islands, University of La Laguna, Tenerife 38071, Spain; and INSERM UMRS 1138 (N.J., N.F.), Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris 75006, France.
Diego
D
Alvarez de la Rosa
D000107:Acetylation; D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D056004:Molecular Dynamics Simulation; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation
D018841:HSP90 Heat-Shock Proteins; D018161:Receptors, Mineralocorticoid; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases