Crosstalk between paralogous ComRS quorum-sensing systems diversifies the competence/bacteriocin networks of oral streptococci

ComRS quorum-sensing systems regulate competence and bacteriocin production in the mutans streptococci that cause dental caries (tooth decay). We recently discovered a new class of ComRS (Type IV) in the oral pathogen Streptococcus sobrinus. We now show that every species of mutans streptococci has at least one Type IV ComRS system. S. mutans, S. ratti, S. macacae, and S. ferus have both a Type II and a Type IV ComRS system; S. criceti has one Type IV ComRS system; and S. downei and S. sobrinus have two Type IV ComRS systems. Gene deletion and reporter assays reveal that, in general, competence is regulated by one ComRS system, while a second ComRS system--when present--regulates bacteriocin production. However, crosstalk in species with two ComRS systems leads to a diverse set of competence/bacteriocin network structures. In S. mutans, for example, the Type IV ComRS can potentiate competence by kickstarting the well-studied Type II system, while the Type II system shows spillover activation of the Type IV system. Differences in ComR DNA binding sequences determine the specificity of the ComR paralogs, and sometimes a single base pair change can integrate the two systems. Our work reveals similarities and differences among the competence/bacteriocin networks in naturally competent streptococci, suggesting that paralogous regulation may provide evolutionary flexibility in genetic networks.