title: The Streptococcus pyogenes NAD(+) glycohydrolase modulates epithelial cell PARylation and HMGB1 release.
abstract: Streptococcus pyogenes uses the cytolysin streptolysin O (SLO) to translocate an enzyme, the S. pyogenes NAD(+) glycohydrolase (SPN), into the host cell cytosol. However, the function of SPN in this compartment is not known. As a complication, many S. pyogenes strains express a SPN variant lacking NAD(+) glycohydrolase (NADase) activity. Here, we show that SPN modifies several SLO- and NAD(+) -dependent host cell responses in patterns that correlate with NADase activity. SLO pore formation results in hyperactivation of the cellular enzyme poly-ADP-ribose polymerase-1 (PARP-1) and production of polymers of poly-ADP-ribose (PAR). However, while SPN NADase activity moderates PARP-1 activation and blocks accumulation of PAR, these processes continued unabated in the presence of NADase-inactive SPN. Temporal analyses revealed that while PAR production is initially independent of NADase activity, PAR rapidly disappears in the presence of NADase-active SPN, host cell ATP is depleted and the pro-inflammatory mediator high-mobility group box-1 (HMGB1) protein is released from the nucleus by a PARP-1-dependent mechanism. In contrast, HMGB1 is not released in response to NADase-inactive SPN and instead the cells release elevated levels of interleukin-8 and tumour necrosis factor-α. Thus, SPN and SLO combine to induce cellular responses subsequently influenced by the presence or absence of NADase activity.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Sukantha
authors.initials: S
authors.lastname: Chandrasekaran
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Caparon
mesh_terms: D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology*; D024243:HMGB1 Protein / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D009244:NAD+ Nucleosidase / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D013297:Streptococcus pyogenes / Q000201:enzymology / Q000502:physiology*
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D011064:Poly Adenosine Diphosphate Ribose; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D009244:NAD+ Nucleosidase
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