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Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection

View ORCID ProfileKai S. Beckwith, Marianne S. Beckwith, Sindre Ullmann, Ragnhild Sætra, Haelin Kim, Anne Marstad, Signe E. Åsberg, Trine A. Strand, Harald A. Stenmark, Trude H. Flo
doi: https://doi.org/10.1101/747014
Kai S. Beckwith
1Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
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  • ORCID record for Kai S. Beckwith
Marianne S. Beckwith
1Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
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Sindre Ullmann
1Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
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Ragnhild Sætra
1Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
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Haelin Kim
1Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
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Anne Marstad
1Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
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Signe E. Åsberg
1Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
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Trine A. Strand
1Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
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Harald A. Stenmark
1Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, University of Oslo, Montebello, 0379 Oslo, Norway.
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Trude H. Flo
1Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
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  • For correspondence: trude.flo@ntnu.no
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Abstract

Mycobacterium tuberculosis (Mtb) is a major global health problem and causes extensive cytotoxicity in patient cells and tissues. Here we define an NLRP3, caspase-1 and gasdermin D-mediated pathway to pyroptosis in human monocytes following exposure to Mtb. We demonstrate an ESX-1 mediated, contact-induced plasma membrane (PM) damage response that occurs during phagocytosis or from the cytosolic side of the PM after phagosomal rupture in Mtb infected cells. This PM injury in turn causes K+ efflux and activation of NLRP3 dependent IL-1β release and pyroptosis, facilitating the spread of Mtb to neighbouring cells. Further we reveal a dynamic interplay of pyroptosis with ESCRT-mediated PM repair. Collectively, these findings reveal a novel mechanism for pyroptosis and spread of infection acting through dual PM disturbances both during and after phagocytosis. We also highlight dual PM damage as a common mechanism utilized by other NLRP3 activators that have previously been shown to act through lysosomal damage.

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Posted August 28, 2019.
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Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection
Kai S. Beckwith, Marianne S. Beckwith, Sindre Ullmann, Ragnhild Sætra, Haelin Kim, Anne Marstad, Signe E. Åsberg, Trine A. Strand, Harald A. Stenmark, Trude H. Flo
bioRxiv 747014; doi: https://doi.org/10.1101/747014
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Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection
Kai S. Beckwith, Marianne S. Beckwith, Sindre Ullmann, Ragnhild Sætra, Haelin Kim, Anne Marstad, Signe E. Åsberg, Trine A. Strand, Harald A. Stenmark, Trude H. Flo
bioRxiv 747014; doi: https://doi.org/10.1101/747014

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