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

• DOI: 10.1073/pnas.1218599110
• Publication Date: 2013-04-23T07:10:22Z
• Authors: Alessandro Michel...; Thekla Cordes; Jenny Ghelfi; Arnaud Pailot; Norbert Reiling; Oliver Goldmann; Tina Binz; André Wegner; Aravind Tallam; Antonio Rausell; Manuel Buttini; Carole L. Linster; Eva Medina; Rudi Balling; Karsten Hiller
• Keywords: Itaconic acid

Immunoresponsive gene 1 ( Irg1 ) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify as the coding for an enzyme producing itaconic acid (also known methylenesuccinic acid) through decarboxylation of cis -aconitate, a tricarboxylic cycle intermediate. Using gain-and-loss-of-function approach both mouse and human immune cells, found expression levels correlating with amounts acid, metabolite previously proposed to have antimicrobial effect. We purified IRG1 protein identified -aconitate decarboxylating activity enzymatic assay. Itaconic organic compound that inhibits isocitrate lyase, key glyoxylate shunt, pathway essential bacterial growth under specific conditions. Here show bacteria expressing such Salmonella enterica Mycobacterium tuberculosis . Furthermore, silencing resulted significantly decreased intracellular well reduced infections. Taken together, our results demonstrate links cellular metabolism defense by catalyzing production.