Acetylation-mediated remodeling of the nucleolus regulates cellular acetyl-CoA responses
Ryan Houston, Shiori Sekine, Michael Calderon, Fayaz Seifuddin, Guanghui Wang, Hiroyuki Kawagishi, Daniela Malide, Yuesheng Li, Marjan Guček, Mehdi Pirooznia, Alissa J. Nelson, Matthew P. Stokes, Jacob Stewart-Ornstein, Steven J. Mullett, Stacy G. Wendell, Simon C. Watkins, Toren Finkel, Yusuke Sekine
Abstract
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.