The NADase-Negative Variant of the <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Toxin NAD<sup>+</sup> Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis

ABSTRACT Virulence factors are often multifunctional and contribute to pathogenesis through synergistic mechanisms. For the human pathogen Streptococcus pyogenes, two factors that act synergistically are the S. pyogenes NAD+ glycohydrolase (SPN) and streptolysin O (SLO). Through distinct mechanisms,...

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Autores principales:	Sukantha Chandrasekaran, Michael G. Caparon
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1e73204988fb4d9f93cfc11cc40a0988
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spelling	oai:doaj.org-article:1e73204988fb4d9f93cfc11cc40a09882021-11-15T15:49:40ZThe NADase-Negative Variant of the <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Toxin NAD<sup>+</sup> Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis10.1128/mBio.02215-152150-7511https://doaj.org/article/1e73204988fb4d9f93cfc11cc40a09882016-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02215-15https://doaj.org/toc/2150-7511ABSTRACT Virulence factors are often multifunctional and contribute to pathogenesis through synergistic mechanisms. For the human pathogen Streptococcus pyogenes, two factors that act synergistically are the S. pyogenes NAD+ glycohydrolase (SPN) and streptolysin O (SLO). Through distinct mechanisms, SLO forms pores in host cell membranes and translocates SPN into the host cell cytosol. Two natural variants of SPN exist, one that exhibits NADase activity and one that lacks this function, and both versions are translocated and act in concert with SLO to cause an accelerated death response in epithelial cells. While NADase+ SPN is known to trigger a metabolic form of necrosis through the depletion of NAD+, the mechanism by which NADase− SPN induces cell death was unknown. In the studies described here, we examined the pathway of NADase− cell death through analysis of activation patterns of mitogen-activated protein kinases (MAPKs). S. pyogenes infection resulted in activation of members of three MAPK subfamilies (p38, ERK, and JNK). However, only JNK was activated in an SLO-specific manner. NADase− SPN induced necrosis in HeLa epithelial cells associated with depolarization of mitochondrial membranes, activation of NF-κB, and the generation of reactive oxygen species. Remarkably, RNA interference (RNAi) silencing of JNK protected cells from NADase−-SPN-mediated necrosis, suggesting that NADase− SPN triggers a form of programmed necrosis dependent on JNK signaling. Taken together, these data demonstrate that SPN acts with SLO to elicit necrosis through two different mechanisms depending on its NADase activity, i.e., metabolic (NADase+) or programmed (NADase−), leading to distinct inflammatory profiles. IMPORTANCE Many bacterial pathogens produce toxins that alter how infected host cells interact with the immune system. For Streptococcus pyogenes, two toxins, a NAD+ glycohydrolase (SPN) and streptolysin O (SLO), act in combination to cause infected cells to die. However, there are two natural forms of SPN, and these variants cause dying cells to produce different types of signaling molecules. The NADase+ form of SPN kills cells by depleting reserves of NAD+ and cellular energy. The other form of SPN lacks this activity (NADase−); thus, the mechanism by which this variant induces toxicity was unknown. Here, we show that infected cells recognize NADase− SPN through a specific signaling molecule called JNK, which causes these cells to undergo a form of cellular suicide known as programmed necrosis. This helps us to understand how different forms of toxins alter host cell signaling to help S. pyogenes cause different types of diseases.Sukantha ChandrasekaranMichael G. CaparonAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 1 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Sukantha Chandrasekaran Michael G. Caparon The NADase-Negative Variant of the <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Toxin NAD<sup>+</sup> Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis
description	ABSTRACT Virulence factors are often multifunctional and contribute to pathogenesis through synergistic mechanisms. For the human pathogen Streptococcus pyogenes, two factors that act synergistically are the S. pyogenes NAD+ glycohydrolase (SPN) and streptolysin O (SLO). Through distinct mechanisms, SLO forms pores in host cell membranes and translocates SPN into the host cell cytosol. Two natural variants of SPN exist, one that exhibits NADase activity and one that lacks this function, and both versions are translocated and act in concert with SLO to cause an accelerated death response in epithelial cells. While NADase+ SPN is known to trigger a metabolic form of necrosis through the depletion of NAD+, the mechanism by which NADase− SPN induces cell death was unknown. In the studies described here, we examined the pathway of NADase− cell death through analysis of activation patterns of mitogen-activated protein kinases (MAPKs). S. pyogenes infection resulted in activation of members of three MAPK subfamilies (p38, ERK, and JNK). However, only JNK was activated in an SLO-specific manner. NADase− SPN induced necrosis in HeLa epithelial cells associated with depolarization of mitochondrial membranes, activation of NF-κB, and the generation of reactive oxygen species. Remarkably, RNA interference (RNAi) silencing of JNK protected cells from NADase−-SPN-mediated necrosis, suggesting that NADase− SPN triggers a form of programmed necrosis dependent on JNK signaling. Taken together, these data demonstrate that SPN acts with SLO to elicit necrosis through two different mechanisms depending on its NADase activity, i.e., metabolic (NADase+) or programmed (NADase−), leading to distinct inflammatory profiles. IMPORTANCE Many bacterial pathogens produce toxins that alter how infected host cells interact with the immune system. For Streptococcus pyogenes, two toxins, a NAD+ glycohydrolase (SPN) and streptolysin O (SLO), act in combination to cause infected cells to die. However, there are two natural forms of SPN, and these variants cause dying cells to produce different types of signaling molecules. The NADase+ form of SPN kills cells by depleting reserves of NAD+ and cellular energy. The other form of SPN lacks this activity (NADase−); thus, the mechanism by which this variant induces toxicity was unknown. Here, we show that infected cells recognize NADase− SPN through a specific signaling molecule called JNK, which causes these cells to undergo a form of cellular suicide known as programmed necrosis. This helps us to understand how different forms of toxins alter host cell signaling to help S. pyogenes cause different types of diseases.
format	article
author	Sukantha Chandrasekaran Michael G. Caparon
author_facet	Sukantha Chandrasekaran Michael G. Caparon
author_sort	Sukantha Chandrasekaran
title	The NADase-Negative Variant of the <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Toxin NAD<sup>+</sup> Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis
title_short	The NADase-Negative Variant of the <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Toxin NAD<sup>+</sup> Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis
title_full	The NADase-Negative Variant of the <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Toxin NAD<sup>+</sup> Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis
title_fullStr	The NADase-Negative Variant of the <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Toxin NAD<sup>+</sup> Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis
title_full_unstemmed	The NADase-Negative Variant of the <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Toxin NAD<sup>+</sup> Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis
title_sort	nadase-negative variant of the <named-content content-type="genus-species">streptococcus pyogenes</named-content> toxin nad<sup>+</sup> glycohydrolase induces jnk1-mediated programmed cellular necrosis
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/1e73204988fb4d9f93cfc11cc40a0988
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The NADase-Negative Variant of the <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Toxin NAD<sup>+</sup> Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis

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