The role of lysine acetylation in metabolic sensing and proteostasis

Post-translational acetylation of lysine residues is a dynamic and reversible modification that plays a pivotal role in regulating protein structure, function, and interactions. This modification is mediated by central metabolite acetyl-CoA and is tightly controlled by the opposing actions of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), including the NAD⁺-dependent sirtuins. As a nutrient-sensing post-translational modification (PTM), acetylation is essential for maintaining cellular homeostasis, particularly by modulating proteostasis and metabolic flexibility-the ability of cells to rewire metabolic pathways in response to fluctuating energy demands and nutrient availability. Dysregulation of acetylation has been implicated in the pathogenesis of metabolic disorders, neurodegenerative diseases, and cancer. Emerging evidence suggests that targeting acetylation-regulating enzymes with small-molecule inhibitors or activators hold promise for elucidating the role of acetylation in metabolic sensing and protein homeostasis. This review examines the regulation of acetylation across various metabolic states, its impact on metabolic adaptability, and its intricate interplay with proteostasis mechanisms. Additionally, it highlights the role of site-specific acetylation dynamics and sirtuin biology shaping metabolic regulation, providing key insights into the mechanisms underlying metabolic disorders and their progression. Understanding the regulatory mechanisms governing acetylation-dependent metabolic sensing could facilitate the development of precision therapeutics to restore metabolic homeostasis.