Article (Scientific journals)
Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production
Michelucci, Alessandro; Cordes, Thekla; Ghelfi, Jenny et al.
2013In Proceedings of the National Academy of Sciences of the United States of America
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Abstract :
[en] 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.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group)
- Luxembourg Centre for Systems Biomedicine (LCSB): Enzymology & Metabolism (Linster Group)
- Luxembourg Centre for Systems Biomedicine (LCSB): Computational Biology (Del Sol Group)
Luxembourg Centre for Systems Biomedicine (LCSB): Metabolomics (Hiller Group)
Disciplines :
Microbiology
Biochemistry, biophysics & molecular biology
Author, co-author :
Michelucci, Alessandro ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Cordes, Thekla ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Ghelfi, Jenny ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Pailot, Arnaud ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Reiling, Norbert
Goldmann, Oliver
Binz, Tina
Wegner, André ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Tallam, Aravind ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Rausell, Antonio
Buttini, Manuel ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Linster, Carole  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Medina, Eva
Balling, Rudi ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Hiller, Karsten ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
More authors (5 more) Less
External co-authors :
yes
Language :
English
Title :
Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production
Publication date :
22 April 2013
Journal title :
Proceedings of the National Academy of Sciences of the United States of America
ISSN :
1091-6490
Publisher :
National Academy of Sciences, Washington, United States - District of Columbia
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 28 May 2013

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