Itaconate is an important antimicrobial and immunoregulatorymetaboliteinvolved in host-pathogen interactions. A key mechanistic actionof itaconate is through the covalent modification of cysteine residuesvia Michael addition, resulting in "itaconation". However,it is unclear whether itaconate has other regulatory mechanisms. Inthis work, we discovered a novel type of post-translational modificationby promiscuous antibody enrichment and data analysis with the open-searchstrategy and further confirmed it as the lysine "itaconylation".We showed that itaconylation and its precursor metabolite itaconyl-CoAundergo significant upregulation upon lipopolysaccharides (LPS) stimulationin RAW264.7 macrophages. Quantitative proteomics identified itaconylationsites in multiple functional proteins, including glycolytic enzymesand histones, some of which were confirmed by synthetic peptide standards.The discovery of lysine itaconylation opens up new areas for studyinghow itaconate participates in immunoregulation via protein post-translationalmodification.
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