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

by Ryan Houston, Shiori Sekine, Michael J. Calderon, Fayaz Seifuddin, Guanghui Wang, Hiroyuki Kawagishi, Daniela A. Malide, Yuesheng Li, Marjan Gucek, Mehdi Pirooznia, Alissa J. Nelson, Matthew P. Stokes, Jacob Stewart-Ornstein, Steven J. Mullett, Stacy G. Wendell, Simon C. Watkins, Toren Finkel, Yusuke Sekine

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.

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Paper source
Plos Journal

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