Proteomics

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Gasdermin D mediates host cell death but not interleukin-1β secretion in Mycobacterium tuberculosis infected macrophages


ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Macrophage

SUBMITTER: Prerana Wagle  

LAB HEAD: Jan Rybniker

PROVIDER: PXD029017 | Pride | 2022-02-17

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
1986.sps Other
1986_dDIA.sne Other
1986_dDIA_Report_PC.setup.txt Txt
1986_dDIA_Report_PC.tsv Tabular
1986_dDIA_Report_PEP.setup.txt Txt
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Publications

Gasdermin D mediates host cell death but not interleukin-1β secretion in Mycobacterium tuberculosis-infected macrophages.

Theobald Sebastian J SJ   Gräb Jessica J   Fritsch Melanie M   Suárez Isabelle I   Eisfeld Hannah S HS   Winter Sandra S   Koch Maximilian M   Hölscher Christoph C   Pasparakis Manolis M   Kashkar Hamid H   Rybniker Jan J  

Cell death discovery 20211030 1


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 mech  ...[more]

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