Osmoregulation via Cyclic di-AMP signaling

Nucleotide second messengers allow cells to transduce external signals into cellular responses by modulating the activity of a variety of protein and riboswitch receptors. Cyclic di-AMP has been found to impact on a wide array of cellular processes including resistance to acid, heat, antibiotics, osmolarity changes and connected to central metabolism, peptidoglycan homeostasis, virulence, biofilm formation, immunomodulation, sporulation, DNA repair, and growth. Unusual for a second messenger however, it is essential for growth under normal culture conditions but toxic when present in high levels for several bacteria. Interestingly high osmolarity conditions can stabilize cells devoid of cyclic di-AMP but inhibit the growth of cells with high cyclic di-AMP. Screens have identified a number of cyclic di-AMP binding receptors, and genetic suppressor analyses have uncovered mutations that restore normal growth in high or low cyclic di-AMP mutant strains. The most cyclic di-AMP-binding receptors characterized thus far in various bacteria are involved in potassium or compatible solute uptake. Taken together, results from several bacteria suggest that osmoregulation is a key conserved function of this nucleotide messenger, which will be the focus of this chapter.