Gasdermin D mediates host cell death but not interleukin-1β secretion in Mycobacterium tuberculosis-infected macrophages.
Journal
Cell death discovery
ISSN: 2058-7716
Titre abrégé: Cell Death Discov
Pays: United States
ID NLM: 101665035
Informations de publication
Date de publication:
30 Oct 2021
30 Oct 2021
Historique:
received:
19
08
2021
accepted:
14
10
2021
revised:
12
10
2021
entrez:
31
10
2021
pubmed:
1
11
2021
medline:
1
11
2021
Statut:
epublish
Résumé
Necrotic cell death represents a major pathogenic mechanism of Mycobacterium tuberculosis (Mtb) infection. It is increasingly evident that Mtb induces several types of regulated necrosis but how these are interconnected and linked to the release of pro-inflammatory cytokines remains unknown. Exploiting a clinical cohort of tuberculosis patients, we show here that the number and size of necrotic lesions correlates with IL-1β plasma levels as a strong indicator of inflammasome activation. Our mechanistic studies reveal that Mtb triggers mitochondrial permeability transition (mPT) and subsequently extensive macrophage necrosis, which requires activation of the NLRP3 inflammasome. NLRP3-driven mitochondrial damage is dependent on proteolytic activation of the pore-forming effector protein gasdermin D (GSDMD), which links two distinct cell death machineries. Intriguingly, GSDMD, but not the membranolytic mycobacterial ESX-1 secretion system, is dispensable for IL-1β secretion from Mtb-infected macrophages. Thus, our study dissects a novel mechanism of pathogen-induced regulated necrosis by identifying mitochondria as central regulatory hubs capable of delineating cytokine secretion and lytic cell death.
Identifiants
pubmed: 34718331
doi: 10.1038/s41420-021-00716-5
pii: 10.1038/s41420-021-00716-5
pmc: PMC8557205
doi:
Types de publication
Journal Article
Langues
eng
Pagination
327Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB1403
Organisme : Deutsches Zentrum für Infektionsforschung (German Center for Infection Research)
ID : TTU 02.806
Informations de copyright
© 2021. The Author(s).
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