Universität zu Köln

Theobald, Sebastian J., Graeb, Jessica, Fritsch, Melanie, Suarez, Isabelle, Eisfeld, Hannah S., Winter, Sandra, Koch, Maximilian, Hoelscher, Christoph, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Kashkar, Hamid and Rybniker, Jan (2021). Gasdermin D mediates host cell death but not interleukin-1 beta secretion in Mycobacterium tuberculosis-infected macrophages. Cell Death Discov., 7 (1). LONDON: SPRINGERNATURE. ISSN 2058-7716

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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-1 beta 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-1 beta 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Theobald, Sebastian J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Graeb, Jessica UNSPECIFIED UNSPECIFIED UNSPECIFIED Fritsch, Melanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Suarez, Isabelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Eisfeld, Hannah S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Winter, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Koch, Maximilian UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoelscher, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Kashkar, Hamid UNSPECIFIED UNSPECIFIED UNSPECIFIED Rybniker, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-579731
DOI:	10.1038/s41420-021-00716-5
Journal or Publication Title:	Cell Death Discov.
Volume:	7
Number:	1
Date:	2021
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	2058-7716
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NLRP3 INFLAMMASOME; MITOCHONDRIAL; PYROPTOSIS; APOPTOSIS; TRIGGER; NECROPTOSIS; RESISTANCE; INHIBITOR; CASPASE-8; LIVE Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/57973