Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels

Cordes, Thekla; Wallace, Martina; Michelucci, Alessandro; Divakaruni, Ajit S.; Sapcariu, Sean C.; Sousa, Carole; Koseki, Haruhiko; Cabrales, Pedro; Murphy, Anne N.; Hiller, Karsten; Metallo, Christian M.

doi:10.1074/jbc.m115.685792

Cited by 393 publications

(428 citation statements)

References 50 publications

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“…Itaconate is reported to have anti-microbial activity, as it inhibits bacterial isocitrate lyase in the glyoxylate shunt, a pathway not found in humans (McFadden and Purohit, 1977; Patel and McFadden, 1978; Williams et al, 1971). More recently, itaconate has been described as an anti-inflammatory metabolite whose activity is mediated in part by its ability to inhibit SDH and prevent ROS generation (Cordes et al, 2016; Lampropoulou et al, 2016; Luan and Medzhitov, 2016). Little is known about the fate of itaconate after immune activation.…”

Section: Discussionmentioning

confidence: 99%

The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12

Shen

Campanello

Flicker

et al. 2017

Cell

111

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Summary CLYBL encodes a ubiquitously expressed mitochondrial enzyme, conserved across all vertebrates, whose cellular activity and pathway assignment are unknown. Its homozygous loss is tolerated in seemingly healthy individuals, with reduced circulating B12 levels being the only and consistent phenotype reported to date. Here, by combining enzymology, structural biology and activity-based metabolomics we report that CLYBL operates as a citramalyl-CoA lyase in mammalian cells. Cells lacking CLYBL accumulate citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that includes itaconate, a recently identified human antimicrobial metabolite and immunomodulator. We report that CLYBL loss leads to a cell autonomous defect in the mitochondrial B12 metabolism and that itaconyl-CoA is a cofactor-inactivating, substrate-analogue inhibitor of the mitochondrial B12-dependent methylmalonyl-CoA mutase (MUT). Our work de-orphans the function of human CLYBL and reveals that a consequence of exposure to the immunomodulatory metabolite itaconate is B12 inactivation.

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Section: Discussionmentioning

confidence: 99%

The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12

Shen

Campanello

Flicker

et al. 2017

Cell

111

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“…It was demonstrated over sixty years ago that itaconate can competitively inhibit succinate dehydrogenase (SDH) function (Ackermann and Potter, 1949). Recently, this inhibition has been shown to be relevant in mammalian cells, as exogenous addition of itaconate to resting macrophages, activated macrophages, or the lung adenocarcinoma cell line A549 is sufficient to induce succinate accumulation (Cordes et al, 2016). Furthermore, Irg1 / Acod1 KO BMDMs have significantly decreased succinate accumulation after treatment with LPS (Cordes et al, 2016; Lampropoulou et al, 2016).…”

Section: Itaconate As a Regulator Of Immune Cell Bioenergeticsmentioning

confidence: 99%

Food Fight: Role of Itaconate and Other Metabolites in Antimicrobial Defense

2016

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“…Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines 2 , including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase 2,3 , yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined.…”

mentioning

confidence: 99%

Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis

Bambousková

Gorvel

Lampropoulou

et al. 2018

Nature

497

568

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Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite2. Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines2, including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase2,3, yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFE2L2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of IκBζ protein induction. The regulation of IκBζ is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17–IκBζ-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI–IκBζ regulatory axis could be an important new strategy for the treatment of IL-17–IκBζ-mediated autoimmune diseases.

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Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels

Cited by 393 publications

References 50 publications

The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12

The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12

Food Fight: Role of Itaconate and Other Metabolites in Antimicrobial Defense

Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis

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