Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production

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.

• Publication year

  2013

• Venue

  Proceedings of the National Academy of Sciences of the United States of America

• Publication date

  2013-04-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1073/pnas.1218599110PMID 23610393PMCID PMC3651434
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2010cited by this paper
• The Proinflammatory Cytokine-Induced IRG1 Protein Associates with Mitochondria

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  2009cited by this paper
• EnsemblCompara GeneTrees: Complete, duplication-aware phylogenetic trees in vertebrates.

  2009cited by this paper
• Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-beta.

  2009cited by this paper
• Functional Characterization of a Vitamin B12-Dependent Methylmalonyl Pathway in Mycobacterium tuberculosis: Implications for Propionate Metabolism during Growth on Fatty Acids

  2008cited by this paper
• Macrophage activation and polarization.

  2008cited by this paper
• Cloning and functional characterization of the cis-aconitic acid decarboxylase (CAD) gene from Aspergillus terreus

  2008cited by this paper
• Identification of outer membrane proteins of Mycobacterium tuberculosis.

  2008cited by this paper
• Transcription factor expression in lipopolysaccharide-activated peripheral-blood-derived mononuclear cells

  2007cited by this paper
• Mycobacterium paratuberculosis, Mycobacterium smegmatis, and lipopolysaccharide induce different transcriptional and post‐transcriptional regulation of the IRG1 gene in murine macrophages

  2006cited by this paper
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  2006cited by this paper
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  2006cited by this paper
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  2006cited by this paper
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  2005cited by this paper
• The chemokine system in diverse forms of macrophage activation and polarization.

  2004cited by this paper
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  2003cited by this paper
• Immune-responsive gene 1 is a novel target of progesterone receptor and plays a critical role during implantation in the mouse.

  2003cited by this paper
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  2002cited by this paper
• Mycobacterium tuberculosis: here today, and here tomorrow

  2001cited by this paper
• Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis

  2000cited by this paper
• Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase

  2000cited by this paper
• Characterization of Activity and Expression of Isocitrate Lyase in Mycobacterium avium andMycobacterium tuberculosis

  1999cited by this paper
• Nitric Oxide Sensitivity of the Aconitases*

  1997cited by this paper
• Aconitases: a class of metalloproteins highly sensitive to nitric oxide synthesis.

  1996cited by this paper
• Cloning and analysis of gene regulation of a novel LPS-inducible cDNA

  1995cited by this paper
• Itaconate biosynthesis in Aspergillus terreus

  1995cited by this paper
• Nitric oxide synthases in mammals.

  1994influential reference
• An immortalized cell line expresses properties of activated microglial cells

  1992cited by this paper
• Effect of exogenous and endogenous nitric oxide on mitochondrial respiration of rat hepatocytes.

  1991cited by this paper
• Glyoxylate bypass enzymes in Yersinia species and multiple forms of isocitrate lyase in Yersinia pestis

  1981cited by this paper
• Caenorhabditis elegans and Ascaris suum: inhibition of isocitrate lyase by itaconate.

  1978influential reference
• Functional macrophage cell lines transformed by Abelson leukemia virus.

  1978cited by this paper
• Itaconate, an isocitrate lyase-directed inhibitor in Pseudomonas indigofera

  1977influential reference
• Characteristics of a human cell line transformed by DNA from human adenovirus type 5.

  1977cited by this paper
• In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors.

  1973cited by this paper
• Biosynthesis of itaconic acid in Aspergillus terreus. I. Tracer studies with C14-labeled substrates.

  1957cited by this paper

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