Prevailing concepts of c-di-GMP signaling.

Recently, the list of ubiquitous bacterial secondary messengers which include cAMP and ppGpp has been extended by 3',5'-cyclic diguanylic acid (c-di-GMP). C-di-GMP metabolism is tuned by the tightly controlled activity of diguanylate cyclases and c-di-GMP-specific phosphodiesterases. As c-di-GMP-metabolizing enzymes are not only found frequently in bacterial genomes, but also are often numerous in individual genomes, the c-di-GMP metabolic network is highly complex whereby signaling specificity is adjusted on the level of expression, enzymatic activity, protein localization and, most likely, receptor affinity. The targets of c-di-GMP, which include protein and RNA receptors, are subsequently being unraveled. Besides the transition between sessility and motility, probably the most ancient regulatory control of bacterial behavior by c-di-GMP, many more phenotypes such as virulence are affected by c-di-GMP. However, the exact molecular mechanisms of c-di-GMP action remain to be discovered.