Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production
Open accessAbstract
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.
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Activated macrophages increase expression of aconitate decarboxylase 1 (IRG1), which produces itaconate from decarboxylation of TCA cycle-derived aconitate.
“For example, activated macrophages increase expression of the enzyme aconitate decarboxylase 1 (previously known as IRG1), which produces itaconate from the decarboxylation of TCA cycle–derived aconitate, an intermediate in the conversion of citrate to isocitrate (199).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [199]
Itaconate is an α,β-unsaturated carbonyl compound and a potential Michael acceptor that could undergo nucleophilic attack by the thiolate ion of protein cysteine residues.
“It is also important to note that itaconate is an α,β-unsaturated carbonyl compound, making it a potential Michael acceptor that could undergo nucleophilic attack by the thiolate ion of protein cysteine residues, as such the methyl esterification of the proximal carboxyl group conjugated to the alkene would be predicted to increase the electrophilicity of itaconate63.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [63]
In mammals, itaconate is produced through the decarboxylation of the TCA cycle intermediate cis-aconitate, catalyzed by mammalian cis-aconitate decarboxylase (CAD, also known as IRG1 protein) encoded by immunoresponsive gene 1 (IRG1).
“In mammals, itaconate is pro-duced through the decarboxylation of the TCA cycle intermediate cis-aconitate, which is catalyzed by mammalian cis-aconitate decarboxylase (CAD, also known as immune-responsive gene 1 (IRG1) protein) encoded by immunoresponsive gene 1 (IRG1) (20).”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [20]
A549 cells do not express IRG1.
“because A549 cells do not express IRG1 (20)”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [20]
Itaconate-mediated succinate accumulation occurs even in the absence of an active inflammatory signaling cascade.
“they suggest that itaconate-mediated succinate accumulation occurs even in the absence of an active inflammatory signaling cascade.”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [20]
Itaconate exhibits an antibiotic function via inhibition of isocitrate lyase, a key enzyme of the glyoxylate shunt needed by many bacteria to survive during infection.
“Itaconate exhibits an antibiotic function (20) via inhibition of isocitrate lyase, a key enzyme of the glyoxylate shunt needed by many bacteria to survive during infection (21)(22)(23).”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [20]
LPS-activated murine macrophages produce up to 8 mM intracellular itaconate.
“LPS-activated murine macrophages produced up to 8 mM intracellular itaconate (20)”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [20]
Itaconate is produced by mammalian CAD activity on cis-aconitate.
“Itaconate was only recently identified as an endogenous mammalian biochemical (19), and subsequent studies demonstrated that this molecule was produced by mammalian CAD activity on cis-aconitate (20).”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [20]
Under inflammatory conditions such as LPS stimulation, mammalian CAD catalyzes the decarboxylation of cis-aconitate to produce itaconate.
“Under inflammatory conditions, such as LPS stimulation, mammalian CAD catalyzes the decarboxylation of the TCA cycle intermediate cis-aconitate to produce itaconate.”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [20]
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Garaude, J. (2019) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.09.010 · Cited by 33 · see citing works
Glutaminases as a Novel Target for SDHB-Associated Pheochromocytomas/Paragangliomas
Sarkadi, B., Meszaros, K., Krencz, I., Canu, L., Krokker, L., Zakarias, S., Barna, G., Sebestyen, A., Papay, J., Hujber, Z., et al. (2020) · Cancers · doi:10.3390/cancers12030599 · Cited by 23 · see citing works
- Authors
- Michelucci, A., Cordes, T., Ghelfi, J., Pailot, A., Reiling, N., Goldmann, O., Binz, T., Wegner, A., Tallam, A., Rausell, A., Buttini, M., Linster, C. L., Medina, E., Balling, R., & Hiller, K.
- Affiliations
- University of Luxembourg (LU)
- Research Center Borstel - Leibniz Lung Center (DE)
- Helmholtz Centre for Infection Research (DE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-04-22
- Volume
- 110
- Issue
- 19
- Pages
- 7820-7825
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3651434
- OpenAlex
- W1975556592
- Cited by
- 1,191
- References
- 48
- Citations by year
- 2026: 129 · 2025: 135 · 2024: 168 · 2023: 117 · 2022: 125 · 2021: 114 · 2020: 111 · 2019: 79 · 2018: 66 · 2017: 55 · 2016: 43 · 2015: 29 · 2014: 17 · 2013: 3
- FWCI
- 16.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- HZI (Helmholtz Centre for Infection Research) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Keywords
- IRG1, itaconic acid, macrophages, glyoxylate cycle, antimicrobial activity, Salmonella enterica, Mycobacterium tuberculosis, bacterial growth inhibition, inflammation, TCA cycle
- MeSH terms
- Animals, Carboxy-Lyases, Catalysis, Cell Line, Gene Expression Regulation, Humans, Hydro-Lyases, Inflammation, Macrophages, Mice, Inbred C57BL, Monocytes, Mycobacterium tuberculosis, Proteins, Succinates, Lipopolysaccharide Receptors, RNA, Small Interfering, Green Fluorescent Proteins, Mice, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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