Abstract
The Streptococcus pyogenes NAD-glycohydrolase (SPN) is a toxic enzyme that is introduced into infected host cells by the cytolysin-mediated translocation pathway. However, how S. pyogenes protects itself from the self-toxicity of SPN had been unknown. In this report, we describe immunity factor for SPN (IFS), a novel endogenous inhibitor that is essential for SPN expression. A small protein of 161 amino acids, IFS is localized in the bacterial cytoplasmic compartment. IFS forms a stable complex with SPN at a 1:1 molar ratio and inhibits SPN's NAD-glycohydrolase activity by acting as a competitive inhibitor of its β-NAD+ substrate. Mutational studies revealed that the gene for IFS is essential for viability in those S. pyogenes strains that express an NAD-glycohydrolase activity. However, numerous strains contain a truncated allele of ifs that is linked to an NAD-glycohydrolase−deficient variant allele of spn. Of practical concern, IFS allowed the normally toxic SPN to be produced in the heterologous host Escherichia coli to facilitate its purification. To our knowledge, IFS is the first molecularly characterized endogenous inhibitor of a bacterial β-NAD+−consuming toxin and may contribute protective functions in the streptococci to afford SPN-mediated pathogenesis.
Highlights
Bacterial pathogens secrete a multitude of factors that are utilized to advance the infectious process
We tested whether spy0166 from S. pyogenes strain JRS4 could support the expression of spn in E. coli when both genes were placed under the control of the arabinose-inducible promoter on the vector pBAD/gIIIB
We have described immunity factor for Streptococcus pyogenes nicotinamide adenine dinucleotide (NAD)-glycohydrolase (SPN) (IFS), a novel endogenous inhibitor of SPN, the secreted NAD-glycohydrolase of S. pyogenes
Summary
Bacterial pathogens secrete a multitude of factors that are utilized to advance the infectious process. A few secreted enzymes are quite promiscuous and have the ability to adversely affect both the microbe and the host cell. Because of this potential selftoxicity, bacteria must develop mechanisms to protect themselves from the deleterious effects of these universally toxic enzymes in order to successfully use them in pathogenesis. The secreted nicotinamide adenine dinucleotide (NAD)–glycohydrolase of Streptococcus pyogenes (SPN, named NGA [1]), has recently been shown to be injected into the host cell cytoplasm via a specialized translocation process known as cytolysin-mediated translocation (CMT) [2,3]. How S. pyogenes manages the potential self-toxicity of SPN is unknown
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