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

2.50
Hdl Handle:
http://hdl.handle.net/10033/299638
Title:
Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production.
Authors:
Michelucci, Alessandro; Cordes, Thekla; Ghelfi, Jenny; Pailot, Arnaud; Reiling, Norbert; Goldmann, Oliver; Binz, Tina; Wegner, André; Tallam, Aravind; Rausell, Antonio; Buttini, Manuel; Linster, Carole L; Medina, Eva ( 0000-0001-9073-0223 ) ; Balling, Rudi; Hiller, Karsten
Abstract:
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.
Affiliation:
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-Belval, Luxembourg.
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.
Journal:
Proceedings of the National Academy of Sciences of the United States of America
Issue Date:
7-May-2013
URI:
http://hdl.handle.net/10033/299638
DOI:
10.1073/pnas.1218599110
PubMed ID:
23610393
Type:
Article
Language:
en
ISSN:
1091-6490
Appears in Collections:
publications of the research group molecular Immunology (MOLI)

Full metadata record

DC FieldValue Language
dc.contributor.authorMichelucci, Alessandroen_GB
dc.contributor.authorCordes, Theklaen_GB
dc.contributor.authorGhelfi, Jennyen_GB
dc.contributor.authorPailot, Arnauden_GB
dc.contributor.authorReiling, Norberten_GB
dc.contributor.authorGoldmann, Oliveren_GB
dc.contributor.authorBinz, Tinaen_GB
dc.contributor.authorWegner, Andréen_GB
dc.contributor.authorTallam, Aravinden_GB
dc.contributor.authorRausell, Antonioen_GB
dc.contributor.authorButtini, Manuelen_GB
dc.contributor.authorLinster, Carole Len_GB
dc.contributor.authorMedina, Evaen_GB
dc.contributor.authorBalling, Rudien_GB
dc.contributor.authorHiller, Karstenen_GB
dc.date.accessioned2013-08-23T11:05:41Zen
dc.date.available2013-08-23T11:05:41Zen
dc.date.issued2013-05-07en
dc.identifier.citationImmune-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.en_GB
dc.identifier.issn1091-6490en
dc.identifier.pmid23610393en
dc.identifier.doi10.1073/pnas.1218599110en
dc.identifier.urihttp://hdl.handle.net/10033/299638en
dc.description.abstractImmunoresponsive 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.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Proceedings of the National Academy of Sciences of the United States of Americaen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshAntigens, CD14en_GB
dc.subject.meshCatalysisen_GB
dc.subject.meshCell Lineen_GB
dc.subject.meshGene Expression Regulationen_GB
dc.subject.meshGreen Fluorescent Proteinsen_GB
dc.subject.meshHEK293 Cellsen_GB
dc.subject.meshHumansen_GB
dc.subject.meshHydro-Lyasesen_GB
dc.subject.meshInflammationen_GB
dc.subject.meshMacrophagesen_GB
dc.subject.meshMiceen_GB
dc.subject.meshMice, Inbred C57BLen_GB
dc.subject.meshMonocytesen_GB
dc.subject.meshMycobacterium tuberculosisen_GB
dc.subject.meshProteinsen_GB
dc.subject.meshRNA, Small Interferingen_GB
dc.subject.meshSuccinatesen_GB
dc.titleImmune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production.en
dc.typeArticleen
dc.contributor.departmentLuxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-Belval, Luxembourg.en_GB
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen_GB

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