Acetylation-mediated remodeling of the nucleolus regulates cellular acetyl-CoA responses

• Published in: PLoS biology Vol. 18; no. 11; p. e3000981
• Main Authors: Houston, Ryan, Sekine, Shiori, Calderon, Michael J, Seifuddin, Fayaz, Wang, Guanghui, Kawagishi, Hiroyuki, Malide, Daniela A, Li, Yuesheng, Gucek, Marjan, Pirooznia, Mehdi, Nelson, Alissa J, Stokes, Matthew P, Stewart-Ornstein, Jacob, Mullett, Steven J, Wendell, Stacy G, Watkins, Simon C, Finkel, Toren, Sekine, Yusuke
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.11.2020; Public Library of Science (PLoS)
• Subjects: Acetates - metabolism; Acetic acid; Acetyl Coenzyme A - biosynthesis; Acetylation; Adenosine triphosphate; Amino acids; Animal tissues; ATP Citrate (pro-S)-Lyase - deficiency; ATP Citrate (pro-S)-Lyase - genetics; ATP Citrate (pro-S)-Lyase - metabolism; Autophagy; Biological activity; Biology and Life Sciences; Biosynthesis; Cell Line; Cell Nucleolus - metabolism; Cell Nucleolus - ultrastructure; Cell proliferation; Chromatin remodeling; Cloning; CRISPR; Deacetylation; Deprivation; Embryo fibroblasts; Engineering and Technology; Enzymes; Exports; Fatty acids; Fibroblasts; Fibrosarcoma; Gene Expression; Gene Knockout Techniques; Glioblastoma; Glioblastoma cells; Glucose; HCT116 Cells; Hepatocytes; Histone Deacetylases - metabolism; Histones; Humans; Hypoxia; Lipids; Lymphocytes; Lymphocytes T; Metabolic flux; Metabolism; Metabolites; Models, Biological; Nuclear Proteins - metabolism; Nucleoli; Nutrient availability; Nutrients; Physical Sciences; Protein Processing, Post-Translational; Proteins; Research and Analysis Methods; Ribosomal Proteins - metabolism; Signal processing; Signal transduction; Tumor cells; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3000981

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.