TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
23
04
2022
accepted:
13
06
2022
pubmed:
22
7
2022
medline:
28
7
2022
entrez:
21
7
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35864246
doi: 10.1038/s42255-022-00605-w
pii: 10.1038/s42255-022-00605-w
pmc: PMC9314259
doi:
Substances chimiques
Succinates
0
itaconic acid
Q4516562YH
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
856-866Subventions
Organisme : NINDS NIH HHS
ID : R01 NS078072
Pays : United States
Informations de copyright
© 2022. The Author(s).
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