C‐di‐GMP: the dawning of a novel bacterial signalling system

Bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) has come to the limelight as a result of the recent advances in microbial genomics and increased interest in multicellular microbial behaviour. Known for more than 15 years as an activator of cellulose synthase in Gluconacetobacter xylinus, c-di-GMP is emerging as a novel global second messenger in bacteria. The GGDEF and EAL domain proteins involved in c-di-GMP synthesis and degradation, respectively, are (almost) ubiquitous in bacterial genomes. These proteins affect cell differentiation and multicellular behaviour as well as interactions between the microorganisms and their eukaryotic hosts and other phenotypes. While the role of GGDEF and EAL domain proteins in bacterial physiology and behaviour has gained appreciation, and significant progress has been achieved in understanding the enzymology of c-di-GMP turnover, many questions regarding c-di-GMP-dependent signalling remain unanswered. Among these, the key questions are the identity of targets of c-di-GMP action and mechanisms of c-di-GMP-dependent regulation. This review discusses phylogenetic distribution of the c-di-GMP signalling pathway in bacteria, recent developments in biochemical and structural characterization of proteins involved in its metabolism, and biological processes affected by c-di-GMP. The accumulated data clearly indicate that a novel ubiquitous signalling system in bacteria has been discovered.