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Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its phosphokinase PknF

Mycobacterium tuberculosis (Mtb) has evolved to evade host innate immunity by interfering with macrophage functions. Interleukin-1β (IL-1β) is secreted by macrophages after the activation of the inflammasome complex and is crucial for host defense against Mtb infections. We have previously shown tha...

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Autores principales: Rastogi, Shivangi, Ellinwood, Sarah, Augenstreich, Jacques, Mayer-Barber, Katrin D., Briken, Volker
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321130/
https://www.ncbi.nlm.nih.gov/pubmed/34324582
http://dx.doi.org/10.1371/journal.ppat.1009712
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author Rastogi, Shivangi
Ellinwood, Sarah
Augenstreich, Jacques
Mayer-Barber, Katrin D.
Briken, Volker
author_facet Rastogi, Shivangi
Ellinwood, Sarah
Augenstreich, Jacques
Mayer-Barber, Katrin D.
Briken, Volker
author_sort Rastogi, Shivangi
collection PubMed
description Mycobacterium tuberculosis (Mtb) has evolved to evade host innate immunity by interfering with macrophage functions. Interleukin-1β (IL-1β) is secreted by macrophages after the activation of the inflammasome complex and is crucial for host defense against Mtb infections. We have previously shown that Mtb is able to inhibit activation of the AIM2 inflammasome and subsequent pyroptosis. Here we show that Mtb is also able to inhibit host cell NLRP3 inflammasome activation and pyroptosis. We identified the serine/threonine kinase PknF as one protein of Mtb involved in the NLRP3 inflammasome inhibition, since the pknF deletion mutant of Mtb induces increased production of IL-1β in bone marrow-derived macrophages (BMDMs). The increased production of IL-1β was dependent on NLRP3, the adaptor protein ASC and the protease caspase-1, as revealed by studies performed in gene-deficient BMDMs. Additionally, infection of BMDMs with the pknF deletion mutant resulted in increased pyroptosis, while the IL-6 production remained unchanged compared to Mtb-infected cells, suggesting that the mutant did not affect the priming step of inflammasome activation. In contrast, the activation step was affected since potassium efflux, chloride efflux and the generation of reactive oxygen species played a significant role in inflammasome activation and subsequent pyroptosis mediated by the Mtb pknF mutant strain. In conclusion, we reveal here that the serine/threonine kinase PknF of Mtb plays an important role in innate immune evasion through inhibition of the NLRP3 inflammasome.
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spelling pubmed-83211302021-07-31 Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its phosphokinase PknF Rastogi, Shivangi Ellinwood, Sarah Augenstreich, Jacques Mayer-Barber, Katrin D. Briken, Volker PLoS Pathog Research Article Mycobacterium tuberculosis (Mtb) has evolved to evade host innate immunity by interfering with macrophage functions. Interleukin-1β (IL-1β) is secreted by macrophages after the activation of the inflammasome complex and is crucial for host defense against Mtb infections. We have previously shown that Mtb is able to inhibit activation of the AIM2 inflammasome and subsequent pyroptosis. Here we show that Mtb is also able to inhibit host cell NLRP3 inflammasome activation and pyroptosis. We identified the serine/threonine kinase PknF as one protein of Mtb involved in the NLRP3 inflammasome inhibition, since the pknF deletion mutant of Mtb induces increased production of IL-1β in bone marrow-derived macrophages (BMDMs). The increased production of IL-1β was dependent on NLRP3, the adaptor protein ASC and the protease caspase-1, as revealed by studies performed in gene-deficient BMDMs. Additionally, infection of BMDMs with the pknF deletion mutant resulted in increased pyroptosis, while the IL-6 production remained unchanged compared to Mtb-infected cells, suggesting that the mutant did not affect the priming step of inflammasome activation. In contrast, the activation step was affected since potassium efflux, chloride efflux and the generation of reactive oxygen species played a significant role in inflammasome activation and subsequent pyroptosis mediated by the Mtb pknF mutant strain. In conclusion, we reveal here that the serine/threonine kinase PknF of Mtb plays an important role in innate immune evasion through inhibition of the NLRP3 inflammasome. Public Library of Science 2021-07-29 /pmc/articles/PMC8321130/ /pubmed/34324582 http://dx.doi.org/10.1371/journal.ppat.1009712 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Rastogi, Shivangi
Ellinwood, Sarah
Augenstreich, Jacques
Mayer-Barber, Katrin D.
Briken, Volker
Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its phosphokinase PknF
title Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its phosphokinase PknF
title_full Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its phosphokinase PknF
title_fullStr Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its phosphokinase PknF
title_full_unstemmed Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its phosphokinase PknF
title_short Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its phosphokinase PknF
title_sort mycobacterium tuberculosis inhibits the nlrp3 inflammasome activation via its phosphokinase pknf
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321130/
https://www.ncbi.nlm.nih.gov/pubmed/34324582
http://dx.doi.org/10.1371/journal.ppat.1009712
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