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The NADase-Negative Variant of the Streptococcus pyogenes Toxin NAD(+) Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis
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 fo...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society of Microbiology
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742715/ https://www.ncbi.nlm.nih.gov/pubmed/26838722 http://dx.doi.org/10.1128/mBio.02215-15 |
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author | Chandrasekaran, Sukantha Caparon, Michael G. |
author_facet | Chandrasekaran, Sukantha Caparon, Michael G. |
author_sort | Chandrasekaran, Sukantha |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4742715 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Society of Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-47427152016-02-13 The NADase-Negative Variant of the Streptococcus pyogenes Toxin NAD(+) Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis Chandrasekaran, Sukantha Caparon, Michael G. mBio Research Article 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. American Society of Microbiology 2016-02-02 /pmc/articles/PMC4742715/ /pubmed/26838722 http://dx.doi.org/10.1128/mBio.02215-15 Text en Copyright © 2016 Chandrasekaran and Caparon. http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0/) , which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Chandrasekaran, Sukantha Caparon, Michael G. The NADase-Negative Variant of the Streptococcus pyogenes Toxin NAD(+) Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis |
title | The NADase-Negative Variant of the Streptococcus pyogenes Toxin NAD(+) Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis |
title_full | The NADase-Negative Variant of the Streptococcus pyogenes Toxin NAD(+) Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis |
title_fullStr | The NADase-Negative Variant of the Streptococcus pyogenes Toxin NAD(+) Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis |
title_full_unstemmed | The NADase-Negative Variant of the Streptococcus pyogenes Toxin NAD(+) Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis |
title_short | The NADase-Negative Variant of the Streptococcus pyogenes Toxin NAD(+) Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis |
title_sort | nadase-negative variant of the streptococcus pyogenes toxin nad(+) glycohydrolase induces jnk1-mediated programmed cellular necrosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742715/ https://www.ncbi.nlm.nih.gov/pubmed/26838722 http://dx.doi.org/10.1128/mBio.02215-15 |
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