BusR is a Bifunctional Transcription Factor Coordinating Both Osmotic Response and Amino Sugar Metabolism in...

Streptococcus mutans, the major causative agent of dental plaque and caries, maintains osmotic balance under hyperosmotic conditions by transporting glycine betaine into the cytoplasm via the BusAB transporter system. This mechanism is coordinated by the c-di-AMP-responsive transcriptional regulator BusR, which represses busAB expression in the absence of osmotic stress. In this study, we systematically characterized the function of BusR in S. mutans UA159. Our experiments showed that deletion of busR resulted not only in high expression of busAB but also in upregulated GlcNAc metabolic genes, specifically nagA/nagB and glmS, which are known to be regulated by transcriptional regulator NagR. The ΔbusR strain utilized GlcNAc as a nutrient more efficiently and exhibited a faster growth rate than the wild-type strain. Combined with results from further experimentation, this suggests that, BusR assumes a dual regulatory role under high-osmolarity conditions: it relieves repression of busAB to increase the transport of the osmoprotectant betaine into cytoplasm, and cooperates with NagR to regulate amino sugar metabolism by regulating the transcription of nagA/nagB and glmS. Consistent with the molecular ruler mechanism previously described for BusR homologs from Streptococcus agalactiae, we observe a similar structural basis that enables BusR to mediate precise, c-di-AMP-dependent modulation of gene transcription. This coordinated regulation of osmoprotection and amino sugar metabolism by BusR may give S. mutans a significant advantage for dealing with osmotic stress within the oral environment.