Regulation of the mazEF toxin-antitoxin module in Staphylococcus aureus and its impact on sigB expression

In Staphylococcus aureus, the sigB operon codes for the alternative sigma factor sigma(B) and its regulators that enable the bacteria to rapidly respond to environmental stresses via redirection of transcriptional priorities. However, a full model of sigma(B) regulation in S. aureus has not yet emerged. Earlier data has suggested that mazEF, a toxin-antitoxin (TA) module immediately upstream of the sigB operon, was transcribed with the sigB operon. Here we demonstrate that the promoter P(mazE) upstream of mazEF is essential for full sigma(B) activity and that instead of utilizing autorepression typical of TA systems, sigB downregulates this promoter, providing a negative-feedback loop for sigB to repress its own transcription. We have also found that the transcriptional regulator SarA binds and activates P(mazE). In addition, P(mazE) was shown to respond to environmental and antibiotic stresses in a way that provides an additional layer of control over sigB expression. The antibiotic response also appears to occur in two other TA systems in S. aureus, indicating a shared mechanism of regulation.