Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PLoS Biol. 2020 Nov 30;18(11):e3000981. doi: 10.1371/journal.pbio.3000981. eCollection 2020 Nov.
The metabolite acetyl-coenzyme A (acetyl-CoA) serves as an essential element for a wide range of cellular functions including adenosine triphosphate (ATP) production, lipid synthesis, and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa histone deacetylases (HDACs). Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.
代谢物乙酰辅酶 A（acetyl-CoA）是多种细胞功能的必需元素，包括三磷酸腺苷（ATP）的产生、脂质合成和蛋白质乙酰化。细胞内乙酰辅酶 A 浓度与营养物质的可用性有关，但细胞对乙酰辅酶 A 水平波动的反应机制仍不清楚。在这里，我们利用 CRISPR 介导的基因编辑和培养基中添加乙酸盐，生成一种细胞系统来选择性地操纵核质中的乙酰辅酶 A 水平。使用该系统和定量组学分析，我们证明乙酰辅酶 A 耗竭会改变核仁的完整性，损害核糖体 RNA 的合成，并引发核糖体蛋白依赖性的 p53 激活。这种核仁重塑似乎是通过 IIa 类组蛋白去乙酰化酶（HDACs）介导的。我们的发现强调了乙酰化介导的核仁控制作为连接乙酰辅酶 A 波动与细胞应激反应的重要枢纽的作用。
