Atlas of lysine acetylation in the mouse

Lysine acetylation has widespread ramifications from genetic regulatory effects to modulation of enzymatic function. With improved acetyl-lysine enrichment technologies and advances in mass spectrometer speed and sensitivity, we present a comprehensive atlas of the mouse acetylome comprising 17,952 unique lysine acetylation sites across 4,340 proteins and 15 tissues. This resource, which nearly doubles the known mouse acetyl-lysine catalog, shows at least 14% of the acetylome is shared across tissues. We focus our investigation on several acetylated proteins, including ribosomal acetylation and its potential to extend ribosomal half-life in the liver and pancreas. Additionally, we identify a novel acetylation event in the active site of carnitine O-acetyltransferase (Crat) that also mirrors tissue-specific Crat activity. By integrating these data with human pathogenic variants, we identify acetyl-lysine residues on cardiac troponin and homogentisate dioxygenase that likely mimic disease-causing mutations. This resource provides a foundational framework for investigating protein acetylation in metabolic health and disease.