Chemoproteomic profiling of itaconate-derived protein modifications

Itaconate is an emerging immunomodulatory metabolite produced in macrophages upon inflammatory activation and exhibits both immunoregulatory and bacterial-regulatory properties. Structurally, itaconate is a reactive α,β-unsaturated carboxylic acid that undergoes Michael addition with nucleophilic cysteine residues in proteins, generating a unique type of covalent post-translational modification termed itaconation. Here, we review recent progress in the systematic identification of itaconation by chemoproteomic methods. These studies have identified an expanding repertoire of itaconation targets in both host cells and pathogens, providing mechanistic insight into how itaconate regulates immune responses and modulates pathogen tolerance. We further highlight the recent discovery of lysine itaconylation, a novel acylation mediated by itaconate, and briefly review chemoproteomic studies that have globally profiled the non-covalent targets of this immunoregulatory metabolite. Collectively, these chemoproteomic efforts provide rich resources to guide future functional studies and deepen our understanding of the multifaceted roles of itaconate in host-pathogen interactions.