Acetylation-mediated remodeling of the nucleolus regulates cellular acetyl-CoA responses.
2020
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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