PMID:26838722

Citation	Chandrasekaran, S and Caparon, MG (2016) The NADase-Negative Variant of the Streptococcus pyogenes Toxin NAD+ Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis. MBio 7
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.
Links	PubMed PMC4742715 Online version:10.1128/mBio.02215-15
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
STRP3:TACY	Contributes to	GO:0008219: cell death	ECO:0000315:		P		Streptolysin o acts synergistically with NADase+ SPN to destroy cell membranes in infected cells and cause necrosis. In cells infected with mutant types of these proteins less then 10% of the cell membranes were destroyed.	complete CACAO 11362
STRPY:Q5R2E0	Contributes to	GO:0008219: cell death	ECO:0000315:		P		NADase acts synergistically with SLO to cause cell death in all essentially all of the cells they infect. Mutant forms of the protein only caused cell death in less then 10% of the infected cells.	complete CACAO 11361

References

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