Discovery of Itaconate-Mediated Lysine Acylation

作者：Dongyang Liu, Weidi Xiao, Haoting Li, Yanling Zhang, Shouli Yuan, Chengxi Li, Suwei Dong, Chu Wang · 发表于：Journal of the American Chemical Society · 年份：2023 · DOI：10.1021/jacs.3c02332 · 被引用次数：51 · 研究领域：Chemical Synthesis and Analysis、Click Chemistry and Applications、Biochemical and Molecular Research

Itaconate is an important antimicrobial and immunoregulatory metabolite involved in host-pathogen interactions. A key mechanistic action of itaconate is through the covalent modification of cysteine residues via Michael addition, resulting in "itaconation". However, it is unclear whether itaconate has other regulatory mechanisms. In this work, we discovered a novel type of post-translational modification by promiscuous antibody enrichment and data analysis with the open-search strategy and further confirmed it as the lysine "itaconylation". We showed that itaconylation and its precursor metabolite itaconyl-CoA undergo significant upregulation upon lipopolysaccharides (LPS) stimulation in RAW264.7 macrophages. Quantitative proteomics identified itaconylation sites in multiple functional proteins, including glycolytic enzymes and histones, some of which were confirmed by synthetic peptide standards. The discovery of lysine itaconylation opens up new areas for studying how itaconate participates in immunoregulation via protein post-translational modification.