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

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

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.