Acetylation-induced proteasomal degradation of the activated glucocorticoid receptor limits hormonal signaling
Aishwarya Iyer-Bierhoff,
Martin Wieczorek,
Sina Marielle Peter,
Dima Ward,
Martin Bens,
Sabine Vettorazzi,
Karl-Heinz Guehrs,
Jan P. Tuckermann,
Thorsten Heinzel
Affiliations
Aishwarya Iyer-Bierhoff
Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany
Martin Wieczorek
Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany
Sina Marielle Peter
Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany
Dima Ward
Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany
Martin Bens
Core Facility Next Generation Sequencing, Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany
Sabine Vettorazzi
Institute of Comparative Molecular Endocrinology (CME), Ulm University, Helmholtzstrasse 8/1, 89081 Ulm, Germany
Karl-Heinz Guehrs
Core Facility Proteomics, Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany
Jan P. Tuckermann
Institute of Comparative Molecular Endocrinology (CME), Ulm University, Helmholtzstrasse 8/1, 89081 Ulm, Germany
Thorsten Heinzel
Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany; Corresponding author
Summary: Glucocorticoid (GC) signaling is essential for mounting a stress response, however, chronic stress or prolonged GC therapy downregulates the GC receptor (GR), leading to GC resistance. Regulatory mechanisms that refine this equilibrium are not well understood. Here, we identify seven lysine acetylation sites in the amino terminal domain of GR, with lysine 154 (Lys154) in the AF-1 region being the dominant acetyl-acceptor. GR-Lys154 acetylation is mediated by p300/CBP in the nucleus in an agonist-dependent manner and correlates with transcriptional activity. Deacetylation by NAD+-dependent SIRT1 facilitates dynamic regulation of this mark. Notably, agonist-binding to both wild-type GR and an acetylation-deficient mutant elicits similar short-term target gene expression. In contrast, upon extended treatment, the polyubiquitination of the acetylation-deficient GR mutant is impaired resulting in higher protein stability, increased chromatin association and prolonged transactivation. Taken together, reversible acetylation fine-tunes duration of the GC response by regulating proteasomal degradation of activated GR.
