Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production
0301 basic medicine
: Microbiologie [F11] [Sciences du vivant]
Carboxy-Lyases
Green Fluorescent Proteins
Lipopolysaccharide Receptors
: Biochemistry, biophysics & molecular biology [F05] [Life sciences]
Antigens, CD14
Catalysis
Monocytes
Cell Line
Mice
03 medical and health sciences
Animals
Humans
: Microbiology [F11] [Life sciences]
RNA, Small Interfering
: Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant]
Hydro-Lyases
Inflammation
Macrophages
Proteins
Succinates
Mycobacterium tuberculosis
3. Good health
Mice, Inbred C57BL
HEK293 Cells
Gene Expression Regulation
DOI:
10.1073/pnas.1218599110
Publication Date:
2013-04-23T07:10:22Z
AUTHORS (15)
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.
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