More than two components: complexities in bacterial phosphosignaling

For over 40 years, the two-component systems (TCSs) have taken front and center in our thinking about the signaling mechanisms by which bacteria sense and respond to their environment. In contrast, phosphorylation on Ser/Thr and Tyr ( O -phosphorylation) was long thought to be mostly restricted to eukaryotes and a somewhat accessory signaling mechanism in bacteria. Several recent studies exploring systems aspects of bacterial O -phosphorylation, however, now show that it is in fact pervasive, with some bacterial proteomes as highly phosphorylated as those of eukaryotes. Labile, non-canonical protein phosphorylation sites on Asp, Arg, and His are now also being identified in large numbers in bacteria and first cellular functions are discovered. Other phosphomodifications on Cys, Glu, and Lys remain largely unexplored. The surprising breadth and complexity of bacterial phosphosignaling reveals a vast signaling capacity, the full scope of which we may only now be beginning to understand but whose functions are likely to affect all aspects of bacterial physiology and pathogenesis.