Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production
By A. Michelucci, Thekla Cordes, Jenny Ghelfi, Arnaud Pailot, N. Reiling, O. Goldmann, T. Binz, A. Wegner, Aravind Tallam, A. Rausell and 5 more. Proceedings of the National Academy of Sciences of the United States of America, 2013
1,083 citations recorded by the source corpus.
Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an enzyme producing itaconic acid (also known as methylenesuccinic acid) through the decarboxylation of cis-aconitate, a tricarboxylic acid cycle intermediate. Using a gain-and-loss-of-function approach in both mouse and human immune cells, we found Irg1 expression levels correlating with the amounts of itaconic acid, a metabolite previously proposed to have an antimicrobial effect. We purified IRG1 protein and identified its cis-aconitate decarboxylating activity in an enzymatic assay. Itaconic acid is an organic compound that inhibits isocitrate lyase, the key enzyme of the glyoxylate shunt, a pathway essential for bacterial growth under specific conditions. Here we show that itaconic acid inhibits the growth of bacteria expressing isocitrate lyase, such as Salmonella enterica and Mycobacterium tuberculosis. Furthermore, Irg1 gene silencing in macrophages resulted in significantly decreased intracellular itaconic acid levels as well as significantly reduced antimicrobial activity during bacterial infections. Taken together, our results demonstrate that IRG1 links cellular metabolism with immune defense by catalyzing itaconic acid production.
Subfields: Biological Psychiatry, Immunology
View Paper: https://www.semanticscholar.org/paper/d8d6f49dcfc0ba1c5c31d4ff92ca85c1fc9ee365
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In Biological Psychiatry
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- Russell G. Jones
- Edward J. Pearce
- F. Munari
- R. Sánchez-Rodríguez
- Tommaso Scolaro
- Michael S. Diamond
- A. Viola
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Citations in the corpus
- Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “…from cis-aconitate in the TCA cycle of macrophages and is activated by a variety of factors, including LPS and other Toll-like receptor ligands and cytokines, such as type I and type II interferons (Shin et al., 2011; Strelko et al., 2011; Sugimoto et al., 2011; Michelucci et al., 2013).”
- Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. (2015, methodology): “It is important to point out that in the context of greatly reduced Idh activity and associated reduction of carbon flow to AKG, citric acid is redirected to serve as a precursor for itaconic acid synthesis, an important anti-microbial metabolite identified recently (Michelucci et al., 2013).”
- Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation (2016, background): “, 2011) and certain infections (Michelucci et al., 2013) and is generated by the mitochondria-associated enzyme (Degrandi et al.”
- The Metabolic Signature of Macrophage Responses (2019, background): “This occurs through a strong upregulation of the enzyme aconitate decarboxylase 1 (ACOD1), originally called immune-responsive gene 1 protein (IRG1) (91).”
- MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations (2020, background): “As an illustrative example, IRG1 is expressed almost exclusively in macrophages following activation, and detailed studies demonstrated that it encodes a mitochondrial aconitate de-carboxylase that produces itaconate, an immunometabo-lite (18).”