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Bacterial itaconate degradation promotes pathogenicity

Abstract

Itaconate (methylenesuccinate) was recently identified as a mammalian metabolite whose production is substantially induced during macrophage activation. This compound is a potent inhibitor of isocitrate lyase, a key enzyme of the glyoxylate cycle, which is a pathway required for the survival of many pathogens inside the eukaryotic host. Here we show that numerous bacteria, notably many pathogens such as Yersinia pestis and Pseudomonas aeruginosa, have three genes for itaconate degradation. They encode itaconate coenzyme A (CoA) transferase, itaconyl-CoA hydratase and (S)-citramalyl-CoA lyase, formerly referred to as CitE-like protein. These genes are known to be crucial for survival of some pathogens in macrophages. The corresponding enzymes convert itaconate into the cellular building blocks pyruvate and acetyl-CoA, thus enabling the bacteria to metabolize itaconate and survive in macrophages. The itaconate degradation and detoxification pathways of Yersinia and Pseudomonas are the result of convergent evolution. This work revealed a common persistence factor operating in many pathogenic bacteria.

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Figure 1: Itaconate degradation pathway and the corresponding gene clusters in Y. pestis and P. aeruginosa.
Figure 2: In vitro reconstitution of itaconate degradation pathway with the heterologously produced and purified enzymes from Y. pestis.
Figure 3: In vitro reconstitution of itaconate degradation pathway with the heterologously produced and purified enzymes from P. aeruginosa.

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Acknowledgements

This work was funded by the Deutsche Forschungsgemeinschaft (BE 4822/2-1 and Heisenberg fellowship to I.A.B.). We thank B. Alber, R. Teufel, J. Zarzycki and M. Carter for critical reading the manuscript; W. Buckel for the discussions of the Ich mechanism and G. Fuchs for constant support and discussions during the work and for critically reading the manuscript.

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J.S. performed all of the experiments with Y. pestis proteins. M.Z. performed the experiments with PaCcl and P. aeruginosa cells and cell extracts. P.K.Z. performed the experiments with H. sapiens Ccl. A.F. performed the experiments with PaIct and PaIch and an in vitro reconstruction of P. aeruginosa itaconate conversion. I.A.B. designed research, analyzed data and wrote the paper.

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Correspondence to Ivan A Berg.

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The authors declare no competing financial interests.

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Sasikaran, J., Ziemski, M., Zadora, P. et al. Bacterial itaconate degradation promotes pathogenicity. Nat Chem Biol 10, 371–377 (2014). https://doi.org/10.1038/nchembio.1482

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