Abstract
The transcriptional activity of the glucocorticoid receptor (GR) is co-determined by its ability to recruit a vast and varying number of cofactors. We here identify Striatin-3 (STRN3) as a novel interaction partner of GR that interferes with GR’s ligand-dependent transactivation capacity. Remarkably, STRN3 selectively affects only GR-dependent transactivation and leaves GR-dependent transrepression mechanisms unhampered. We found that STRN3 down-regulates GR transactivation by an additional recruitment of the catalytic subunit of protein phosphatase 2A (PPP2CA) to GR. We hypothesize the existence of a functional trimeric complex in the nucleus, able to dephosphorylate GR at serine 211, a known marker for GR transactivation in a target gene-dependent manner. The presence of STRN3 appears an absolute prerequisite for PPP2CA to engage in a complex with GR. Herein, the C-terminal domain of GR is essential, reflecting ligand-dependency, yet other receptor parts are also needed to create additional contacts with STRN3.
Highlights
Glucocorticoids (GC) exert effects at multiple levels of cellular functionality, including energy metabolism, cell fate and immune response
Since ECI2 is a PPARα/ GRα co-controlled gene[34] and PPARα may be a target of STRN3 (Fig. 4B) it is tempting to speculate that the different regulation of ECI2 might be ascribed to an increased level control of this particular gene promoter
By using a glucocorticoid receptor (GR) mutant of serine 211 (S211) (S211A) we showed that the negative impact of STRN3 on GR transactivation is phosphorylation-dependent
Summary
Glucocorticoids (GC) exert effects at multiple levels of cellular functionality, including energy metabolism, cell fate and immune response. GR-mediated gene promoter activation involves DNA binding of a homodimeric GR on a palindromic GC response element (GRE) in the promoter (simple GRE), from a coordinated DNA binding of a GR/transcription factor complex onto a so-called composite GRE or from a GR/transcription factor tethering mechanism. The latter two mechanisms can form the basis for GR-mediated promoter repression[5, 6]. Exogenous GC treatment induces GR dimer assembly to classic palindromic site-containing promoters of ligand-dependent genes. This event is at the expense of monomeric GR binding which vanishes from promoters of repressed genes[8]. Our data support a role for STRN3 as an important check-point for GR functionality
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