Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production.
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Authors
Michelucci, AlessandroCordes, Thekla
Ghelfi, Jenny
Pailot, Arnaud
Reiling, Norbert
Goldmann, Oliver
Binz, Tina
Wegner, André
Tallam, Aravind
Rausell, Antonio
Buttini, Manuel
Linster, Carole L
Medina, Eva
Balling, Rudi
Hiller, Karsten
Issue Date
2013-05-07
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Show full item recordAbstract
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.Citation
Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. 2013, 110 (19):7820-5 Proc. Natl. Acad. Sci. U.S.A.Affiliation
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-Belval, Luxembourg.PubMed ID
23610393Type
ArticleLanguage
enISSN
1091-6490ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1218599110
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