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  TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages

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. doi:10.1038/s42255-022-00605-w.

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10.1038_s42255-022-00605-w.pdf (Publisher version), 12MB
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 Creators:
Schuster, Ev-Marie1, Author
Epple, Maximilian W.1, Author
Glaser, Katharina M.2, Author
Mihlan, Michael2, Author
Lucht, Kerstin1, Author
Zimmermann, Julia A.1, Author
Bremser, Anna1, Author
Polyzou, Aikaterini3, Author
Obier, Nadine3, Author
Cabezas-Wallscheid, Nina3, Author           
Trompouki, Eirini3, Author           
Ballabio, Andrea4, Author
Vogel, Jörg4, Author
Büscher, Jörg Martin2, Author           
Westermann, Alexander J.4, Author
Rambold, Angelika1, Author           
Affiliations:
1Department of Developmental Immunobiology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243650              
2Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243648              
3Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243641              
4External Organizations, ou_persistent22              

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Free keywords: Antimicrobial responses, Metabolism, Phagocytes
 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.

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Language(s): eng - English
 Dates: 2022-07-21
 Publication Status: Published online
 Pages: -
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s42255-022-00605-w
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Title: Nature Metabolism
Source Genre: Journal
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Publ. Info: London : Springer Nature
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: - Identifier: ISSN: 2522-5812
CoNE: https://pure.mpg.de/cone/journals/resource/2522-5812