Iyer-Bierhoff Aishwarya, Wieczorek Martin, Peter Sina Marielle, Ward Dima, Bens Martin, Vettorazzi Sabine, Guehrs Karl-Heinz, Tuckermann Jan P, Heinzel Thorsten
Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany.
Core Facility Next Generation Sequencing, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
iScience. 2024 Jan 18;27(2):108943. doi: 10.1016/j.isci.2024.108943. eCollection 2024 Feb 16.
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) in the AF-1 region being the dominant acetyl-acceptor. GR-Lys 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.
糖皮质激素（GC）信号传导对于产生应激反应至关重要，然而，慢性应激或长期GC治疗会下调GC受体（GR），导致GC抵抗。调节这种平衡的机制尚不清楚。在这里，我们在GR的氨基末端结构域中鉴定出七个赖氨酸乙酰化位点，AF-1区域中的赖氨酸154（Lys）是主要的乙酰化受体。GR-Lys乙酰化由细胞核中的p300/CBP以激动剂依赖性方式介导，并与转录活性相关。NAD依赖性SIRT1的去乙酰化促进了该标记的动态调节。值得注意的是，激动剂与野生型GR和乙酰化缺陷型突变体的结合都能引发相似的短期靶基因表达。相反，在延长治疗后，乙酰化缺陷型GR突变体的多泛素化受损，导致更高的蛋白质稳定性、增加的染色质结合和延长的反式激活。综上所述，可逆乙酰化通过调节活化GR的蛋白酶体降解来微调GC反应的持续时间。
