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Regulation of the type I protein secretion system by the MisR/MisS two-component system in Neisseria meningitidis

Emory University School of Medicine

ABSTRACT

Neisseria meningitidis, an obligate human pathogen, remains a leading cause of meningitis and fatal sepsis. Meningococci are known to secrete a family of proteins, such as FrpC, with sequence similarity to the repeat-in-toxin (RTX) proteins via the type I secretion system. The meningococcal type I secretion proteins are encoded at two distant genetic loci, NMB1400 (hlyB) and NMB1738/1737 (hlyD/tolC), and are separated from the RTX toxin-like substrates. We have characterized the promoter elements of both hlyB and hlyD by primer extension and lacZ reporter fusions and revealed the growth phase dependent up-regulation of both genes. In addition, we showed that the MisR/MisS two-component system negatively regulates the expression of hlyB and hlyD/tolC. Direct binding of MisR to hlyB and hlyD promoters were demonstrated by electrophoretic mobility shift assay (EMSA), and DNase I protection assays identified MisR binding sites to overlap with the promoter elements. Direct repression of hlyB transcription by MisR was supported by in vitro transcription assays. Mutation in the MisR/S system affected, but did not eliminate, the growth phase up-regulation of hlyB, suggesting additional regulatory mechanisms. Increased secretion of RTX toxin-like proteins were detected in the cell-free media of the misS mutant, indicating that the amount of extracellular RTX toxin-like proteins is, in part, controlled by the abundance of the type I secretion apparatus. This is the first example of a two-component system mediating secretion of cytotoxin family proteins through controlling expression of the type I secretion proteins.

¹ E-mail: ytzeng{at}emory.edu