TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in 
macrophages

Schuster, Ev-Marie; Epple, Maximilian W.; Glaser, Katharina M.; Mihlan, Michael; Lucht, Kerstin; Zimmermann, Julia A.; Bremser, Anna; Polyzou, Aikaterini; Obier, Nadine; Cabezas-Wallscheid, Nina; Trompouki, Eirini; Ballabio, Andrea; Vogel, Jörg; Büscher, Jörg Martin; Westermann, Alexander J.; Rambold, Angelika

doi:10.1038/s42255-022-00605-w

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TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages

MPS-Authors

Schuster, Ev-Marie
Department of Developmental Immunobiology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Epple, Maximilian W.
Department of Developmental Immunobiology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Glaser, Katharina M.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Mihlan, Michael
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lucht, Kerstin
Department of Developmental Immunobiology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Zimmermann, Julia A.
Department of Developmental Immunobiology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Bremser, Anna
Department of Developmental Immunobiology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Polyzou, Aikaterini
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Obier, Nadine
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Cabezas-Wallscheid, Nina
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Trompouki, Eirini
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Büscher, Jörg Martin
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Rambold, Angelika
Department of Developmental Immunobiology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Schuster, E.-M., Epple, M. W., Glaser, K. M., Mihlan, M., Lucht, K., Zimmermann, J. A., et al. (2022). TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages. Nature Metabolism, 4, 856-866. doi:10.1038/s42255-022-00605-w.

Cite as: https://hdl.handle.net/21.11116/0000-000A-C271-B

Abstract

Successful elimination of bacteria in phagocytes occurs in the phago-lysosomal system, but also depends on mitochondrial pathways. Yet, how these two organelle systems communicate is largely unknown. Here we identify the lysosomal biogenesis factor transcription factor EB (TFEB) as regulator for phago-lysosome-mitochondria crosstalk in macrophages. By combining cellular imaging and metabolic profiling, we find that TFEB activation, in response to bacterial stimuli, promotes the transcription of aconitate decarboxylase (Acod1, Irg1) and synthesis of its product itaconate, a mitochondrial metabolite with antimicrobial activity. Activation of the TFEB–Irg1–itaconate signalling axis reduces the survival of the intravacuolar pathogen Salmonella enterica serovar Typhimurium. TFEB-driven itaconate is subsequently transferred via the Irg1-Rab32–BLOC3 system into the Salmonella-containing vacuole, thereby exposing the pathogen to elevated itaconate levels. By activating itaconate production, TFEB selectively restricts proliferating Salmonella, a bacterial subpopulation that normally escapes macrophage control, which contrasts TFEB’s role in autophagy-mediated pathogen degradation. Together, our data define a TFEB-driven metabolic pathway between phago-lysosomes and mitochondria that restrains Salmonella Typhimurium burden in macrophages in vitro and in vivo.