4.8 Article

S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate

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NATURE CHEMICAL BIOLOGY
卷 15, 期 10, 页码 983-+

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-019-0323-5

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资金

  1. National Key Research and Development Projects [2016YFA0501500, 2018YFA0507600]
  2. National Natural Science Foundation of China [21521003, 81490740, 21778004, 21425204, 21672013]
  3. '1,000 Talents Plan' Young Investigator Award

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Itaconate has been recently recognized as an anti-inflammatory metabolite involved in the pathogen-macrophage interface. Due to its weak electrophilicity, itaconate could modify cysteines of the protein KEAP1 and glutathione, which contribute to its anti-inflammatory effect. However, the substrates of itaconate modification in macrophages have not been systematically profiled, which largely impedes the understanding of its roles in immune responses. Here, we developed a specific thiol-reactive probe, 1-OH-Az, for quantitative chemoproteomic profiling of cysteine modifications by itaconate, and provided a global portrait of its proteome reactivity. We found that itaconate covalently modifies key glycolytic enzymes and impairs glycolytic flux mainly through inhibition of fructose-bisphosphate aldolase A (ALDOA). Moreover, itaconate attenuates the inflammatory response in stimulated macrophages by impairing the glycolysis. Our study provides a valuable resource of protein targets of itaconate in macrophages and establishes a negative-feedback link between glycolysis and itaconate, elucidating new functional insights for this anti-inflammatory metabolite.

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