TFEB Induces Mitochondrial Itaconate Synthesis To Suppress Bacterial Growth in Macrophages

Authors

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

Language

English

Publication Date

7-1-2022

Journal

Nature Metabolism

DOI

10.1038/s42255-022-00605-w

PMID

35864246

PMCID

PMC9314259

PubMedCentral® Posted Date

7-21-2022

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Autophagy, Lysosomes, Macrophages, Succinates, Phagocytes, Antimicrobial responses, Metabolism

Published Open-Access

yes

Recommended Citation

Schuster, Ev-Marie; Epple, Maximilian W; Glaser, Katharina M; et al., "TFEB Induces Mitochondrial Itaconate Synthesis To Suppress Bacterial Growth in Macrophages" (2022). Duncan NRI Faculty and Staff Publications. 41.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/41