Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism

F. Chen, W. A.M. Elgaher, M. Winterhoff, K. Büssow, F. H. Waqas, E. Graner, Y. Pires-Afonso, L. Casares Perez, L. de la Vega, N. Sahini, L. Czichon, W. Zobl, T. Zillinger, M. Shehata, S. Pleschka, H. Bähre, C. Falk, A. Michelucci, S. Schuchardt, W. BlankenfeldtA. K.H. Hirsch, F. Pessler*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

Although the immunomodulatory and cytoprotective properties of itaconate have been studied extensively, it is not known whether its naturally occurring isomers mesaconate and citraconate have similar properties. Here, we show that itaconate is partially converted to mesaconate intracellularly and that mesaconate accumulation in macrophage activation depends on prior itaconate synthesis. When added to human cells in supraphysiological concentrations, all three isomers reduce lactate levels, whereas itaconate is the strongest succinate dehydrogenase (SDH) inhibitor. In cells infected with influenza A virus (IAV), all three isomers profoundly alter amino acid metabolism, modulate cytokine/chemokine release and reduce interferon signalling, oxidative stress and the release of viral particles. Of the three isomers, citraconate is the strongest electrophile and nuclear factor-erythroid 2-related factor 2 (NRF2) agonist. Only citraconate inhibits catalysis of itaconate by cis-aconitate decarboxylase (ACOD1), probably by competitive binding to the substrate-binding site. These results reveal mesaconate and citraconate as immunomodulatory, anti-oxidative and antiviral compounds, and citraconate as the first naturally occurring ACOD1 inhibitor. [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)534-546
Number of pages13
JournalNature Metabolism
Volume4
Issue number5
DOIs
Publication statusPublished - May 2022

Keywords

  • Antiviral Agents/metabolism
  • Carboxy-Lyases
  • Catalysis
  • Fumarates/pharmacology
  • Humans
  • Inflammation/metabolism
  • Interferons
  • Macrophages/metabolism
  • Maleates/pharmacology
  • Oxidative Stress

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