ADP-Ribosylation of NLRP3 by <named-content content-type="genus-species">Mycoplasma pneumoniae</named-content> CARDS Toxin Regulates Inflammasome Activity

ABSTRACT The inflammasome is a major regulator of inflammation through its activation of procaspase-1, which cleaves prointerleukin-1β (pro-IL-1β) into its mature form. IL-1β is a critical proinflammatory cytokine that dictates the severity of inflammation associated with a wide spectrum of inflamma...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Santanu Bose, Jesus A. Segovia, Sudha R. Somarajan, Te-Hung Chang, T. R. Kannan, Joel B. Baseman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/921250cbe3eb4a59a1d28b355d922cee
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:921250cbe3eb4a59a1d28b355d922cee
record_format	dspace
spelling	oai:doaj.org-article:921250cbe3eb4a59a1d28b355d922cee2021-11-15T15:47:03ZADP-Ribosylation of NLRP3 by <named-content content-type="genus-species">Mycoplasma pneumoniae</named-content> CARDS Toxin Regulates Inflammasome Activity10.1128/mBio.02186-142150-7511https://doaj.org/article/921250cbe3eb4a59a1d28b355d922cee2014-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02186-14https://doaj.org/toc/2150-7511ABSTRACT The inflammasome is a major regulator of inflammation through its activation of procaspase-1, which cleaves prointerleukin-1β (pro-IL-1β) into its mature form. IL-1β is a critical proinflammatory cytokine that dictates the severity of inflammation associated with a wide spectrum of inflammatory diseases. NLRP3 is a key component of the inflammasome complex, and multiple signals and stimuli trigger formation of the NLRP3 inflammasome complex. In the current study, we uncovered a yet unknown mechanism of NLRP3 inflammasome activation by a pathogen-derived factor. We show that the unique bacterial ADP-ribosylating and vacuolating toxin produced by Mycoplasma pneumoniae and designated community-acquired respiratory distress syndrome (CARDS) toxin activates the NLRP3 inflammasome by colocalizing with the NLRP3 inflammasome and catalyzing the ADP-ribosylation of NLRP3. Mutant full-length CARDS toxin lacking ADP-ribosyltransferase (ADPRT) activity and truncated CARDS toxins unable to bind to macrophages and be internalized failed to activate the NLRP3 inflammasome. These studies demonstrate that CARDS toxin-mediated ADP-ribosylation constitutes an important posttranslational modification of NLRP3, that ADPRT activity of CARDS toxin is essential for NLRP3 inflammasome activation, and that posttranslational ADPRT-mediated modification of the inflammasome is a newly discovered mechanism for inflammasome activation with subsequent release of IL-1β and associated pathologies. IMPORTANCE Inflammation is a fundamental innate immune response to environmental factors, including infections. The inflammasome represents a multiprotein complex that regulates inflammation via its ability to activate specific proinflammatory cytokines, resulting in an effective host protective response. However, excessive release of proinflammatory cytokines can occur following infection that skews the host response to “hyperinflammation” with exaggerated tissue damage. Mycoplasma pneumoniae, a common bacterial airway pathogen, possesses a unique protein toxin with ADP-ribosyltransferase and vacuolating properties capable of reproducing the robust inflammation and cytopathology associated with mycoplasma infection. Here, we show that the toxin uniquely activates the NLRP3 inflammasome by colocalizing with and ADP-ribosylating NLRP3, possibly leading to “hyperinflammation” and thus uncovering a novel target for therapeutic intervention.Santanu BoseJesus A. SegoviaSudha R. SomarajanTe-Hung ChangT. R. KannanJoel B. BasemanAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 6 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Santanu Bose Jesus A. Segovia Sudha R. Somarajan Te-Hung Chang T. R. Kannan Joel B. Baseman ADP-Ribosylation of NLRP3 by <named-content content-type="genus-species">Mycoplasma pneumoniae</named-content> CARDS Toxin Regulates Inflammasome Activity
description	ABSTRACT The inflammasome is a major regulator of inflammation through its activation of procaspase-1, which cleaves prointerleukin-1β (pro-IL-1β) into its mature form. IL-1β is a critical proinflammatory cytokine that dictates the severity of inflammation associated with a wide spectrum of inflammatory diseases. NLRP3 is a key component of the inflammasome complex, and multiple signals and stimuli trigger formation of the NLRP3 inflammasome complex. In the current study, we uncovered a yet unknown mechanism of NLRP3 inflammasome activation by a pathogen-derived factor. We show that the unique bacterial ADP-ribosylating and vacuolating toxin produced by Mycoplasma pneumoniae and designated community-acquired respiratory distress syndrome (CARDS) toxin activates the NLRP3 inflammasome by colocalizing with the NLRP3 inflammasome and catalyzing the ADP-ribosylation of NLRP3. Mutant full-length CARDS toxin lacking ADP-ribosyltransferase (ADPRT) activity and truncated CARDS toxins unable to bind to macrophages and be internalized failed to activate the NLRP3 inflammasome. These studies demonstrate that CARDS toxin-mediated ADP-ribosylation constitutes an important posttranslational modification of NLRP3, that ADPRT activity of CARDS toxin is essential for NLRP3 inflammasome activation, and that posttranslational ADPRT-mediated modification of the inflammasome is a newly discovered mechanism for inflammasome activation with subsequent release of IL-1β and associated pathologies. IMPORTANCE Inflammation is a fundamental innate immune response to environmental factors, including infections. The inflammasome represents a multiprotein complex that regulates inflammation via its ability to activate specific proinflammatory cytokines, resulting in an effective host protective response. However, excessive release of proinflammatory cytokines can occur following infection that skews the host response to “hyperinflammation” with exaggerated tissue damage. Mycoplasma pneumoniae, a common bacterial airway pathogen, possesses a unique protein toxin with ADP-ribosyltransferase and vacuolating properties capable of reproducing the robust inflammation and cytopathology associated with mycoplasma infection. Here, we show that the toxin uniquely activates the NLRP3 inflammasome by colocalizing with and ADP-ribosylating NLRP3, possibly leading to “hyperinflammation” and thus uncovering a novel target for therapeutic intervention.
format	article
author	Santanu Bose Jesus A. Segovia Sudha R. Somarajan Te-Hung Chang T. R. Kannan Joel B. Baseman
author_facet	Santanu Bose Jesus A. Segovia Sudha R. Somarajan Te-Hung Chang T. R. Kannan Joel B. Baseman
author_sort	Santanu Bose
title	ADP-Ribosylation of NLRP3 by <named-content content-type="genus-species">Mycoplasma pneumoniae</named-content> CARDS Toxin Regulates Inflammasome Activity
title_short	ADP-Ribosylation of NLRP3 by <named-content content-type="genus-species">Mycoplasma pneumoniae</named-content> CARDS Toxin Regulates Inflammasome Activity
title_full	ADP-Ribosylation of NLRP3 by <named-content content-type="genus-species">Mycoplasma pneumoniae</named-content> CARDS Toxin Regulates Inflammasome Activity
title_fullStr	ADP-Ribosylation of NLRP3 by <named-content content-type="genus-species">Mycoplasma pneumoniae</named-content> CARDS Toxin Regulates Inflammasome Activity
title_full_unstemmed	ADP-Ribosylation of NLRP3 by <named-content content-type="genus-species">Mycoplasma pneumoniae</named-content> CARDS Toxin Regulates Inflammasome Activity
title_sort	adp-ribosylation of nlrp3 by <named-content content-type="genus-species">mycoplasma pneumoniae</named-content> cards toxin regulates inflammasome activity
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/921250cbe3eb4a59a1d28b355d922cee
work_keys_str_mv	AT santanubose adpribosylationofnlrp3bynamedcontentcontenttypegenusspeciesmycoplasmapneumoniaenamedcontentcardstoxinregulatesinflammasomeactivity AT jesusasegovia adpribosylationofnlrp3bynamedcontentcontenttypegenusspeciesmycoplasmapneumoniaenamedcontentcardstoxinregulatesinflammasomeactivity AT sudharsomarajan adpribosylationofnlrp3bynamedcontentcontenttypegenusspeciesmycoplasmapneumoniaenamedcontentcardstoxinregulatesinflammasomeactivity AT tehungchang adpribosylationofnlrp3bynamedcontentcontenttypegenusspeciesmycoplasmapneumoniaenamedcontentcardstoxinregulatesinflammasomeactivity AT trkannan adpribosylationofnlrp3bynamedcontentcontenttypegenusspeciesmycoplasmapneumoniaenamedcontentcardstoxinregulatesinflammasomeactivity AT joelbbaseman adpribosylationofnlrp3bynamedcontentcontenttypegenusspeciesmycoplasmapneumoniaenamedcontentcardstoxinregulatesinflammasomeactivity
_version_	1718427532099846144

ADP-Ribosylation of NLRP3 by <named-content content-type="genus-species">Mycoplasma pneumoniae</named-content> CARDS Toxin Regulates Inflammasome Activity

Ejemplares similares