Regulation of Staphylococcus aureus pathogenesis via target of RNAIII-activating protein (TRAP)

Staphylococcus aureus can cause disease through the production of toxins. T oxin production is autoinduced by the protein RNAIII-activating protein (RA P) and by the autoinducing peptide (AIP), and is inhibited by RNAIII-inhibi ting peptide (RIP) and by inhibitory AIPs. RAP has been shown to be a usefu l vaccine target site, and RIP and inhibitory AIPs as therapeutic molecules to prevent and suppress S. aureus infections. Development of therapeutic s trategies based on these molecules has been hindered by a lack of knowledge of the molecular mechanisms by which they activate or inhibit virulence. H ere, we show that RAP specifically induces the phosphorylation of a novel 2 1-kDa protein, whereas RIP inhibits its phosphorylation. This protein was t ermed target of RAP (TRAP). The synthesis of the virulence regulatory molec ule, RNAIII, is not activated by RAP in the trap mutant strain, suggesting that RAP activates RNAIII synthesis via TRAP. Phosphoamino acid analysis sh ows that TRAP is histidine-phosphorylated, suggesting that TRAP may be a se nsor of RAP. AIPs upregulate the synthesis of RNAIII also in trap mutant st rains, suggesting that TRAP and AIPs activate RNAIII synthesis via distinct signal transduction pathways. Furthermore, TRAP phosphorylation is down-re gulated in the presence of AIP, suggesting that a network of signal transdu ction pathways regulate S. aureus pathogenesis.