title: Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex.
abstract: Upon binding of a glucocorticoid (GC), the GC receptor (GR) can exert one of three transcriptional regulatory functions. We recently reported that SUMOylation of the GR at position K293 in humans (K310 in mice) within the N-terminal domain is indispensable for GC-induced evolutionary conserved inverted repeated negative GC response element (IR nGRE)-mediated direct transrepression. We now demonstrate that the integrity of this GR SUMOylation site is mandatory for the formation of a GR-small ubiquitin-related modifiers (SUMOs)-SMRT/NCoR1-HDAC3 repressing complex, which is indispensable for NF-κB/AP1-mediated GC-induced tethered indirect transrepression in vitro. Using GR K310R mutant mice or mice containing the N-terminal truncated GR isoform GRα-D3 lacking the K310 SUMOylation site, revealed a more severe skin inflammation than in WT mice. Importantly, cotreatment with dexamethasone (Dex) could not efficiently suppress a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in these mutant mice, whereas it was clearly decreased in WT mice. In addition, in mice selectively ablated in skin keratinocytes for either nuclear receptor corepressor 1 (NCoR1)/silencing mediator for retinoid or thyroid-hormone receptors (SMRT) corepressors or histone deacetylase 3 (HDAC3), Dex-induced tethered transrepression and the formation of a repressing complex on DNA-bound NF-κB/AP1 were impaired. We previously suggested that GR ligands that would lack both (+)GRE-mediated transactivation and IR nGRE-mediated direct transrepression activities of GCs may preferentially exert the therapeutically beneficial GC antiinflammatory properties. Interestingly, we now identified a nonsteroidal antiinflammatory selective GR agonist (SEGRA) that selectively lacks both Dex-induced (+)GRE-mediated transactivation and IR nGRE-mediated direct transrepression functions, while still exerting a tethered indirect transrepression activity and could therefore be clinically lesser debilitating on long-term GC therapy.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, INSERM U964, Illkirch 67404, France;
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Hua
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, INSERM U964, Illkirch 67404, France;
authors.forename: Krishna Priya
authors.initials: KP
authors.lastname: Ganti
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, INSERM U964, Illkirch 67404, France; University of Strasbourg Institute for Advanced Study, Illkirch 67404, France; Collège de France, Illkirch 67404, France chambon@igbmc.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008817:Mice, Mutant Strains; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2 / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D058207:Sumoylation; D000099186:Histone Deacetylase 3
chemical_list: D003907:Dexamethasone; D006655:Histone Deacetylases; D008024:Ligands; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D000099186:Histone Deacetylase 3; C539128:Ncor1 protein, mouse; C539131:Ncor2 protein, mouse
keywords: NF-κB/AP1-mediated GC-induced tethered repression; SUMOylation; glucocorticoid receptor