Acetylation-induced proteasomal degradation of the activated glucocorticoid receptor limits hormonal signaling.

Autor:	Iyer-Bierhoff A; Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany., Wieczorek M; Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany., Peter SM; Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany., Ward D; Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany., Bens M; Core Facility Next Generation Sequencing, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany., Vettorazzi S; Institute of Comparative Molecular Endocrinology (CME), Ulm University, Helmholtzstrasse 8/1, 89081 Ulm, Germany., Guehrs KH; Core Facility Proteomics, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany., Tuckermann JP; Institute of Comparative Molecular Endocrinology (CME), Ulm University, Helmholtzstrasse 8/1, 89081 Ulm, Germany., Heinzel T; Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2024 Jan 18; Vol. 27 (2), pp. 108943. Date of Electronic Publication: 2024 Jan 18 (Print Publication: 2024).
DOI:	10.1016/j.isci.2024.108943
Abstrakt:	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 (Lys 154 ) in the AF-1 region being the dominant acetyl-acceptor. GR-Lys 154 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. Competing Interests: Authors declare that they have no competing interests. (© 2024 The Author(s).)
Databáze:	MEDLINE
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