Cyclic di-GMP signaling-Where did you come from and where will you go?

Microbes including bacteria are required to respond to their often continuously changing ecological niches in order to survive. While many signaling molecules are produced as seemingly circumstantial byproducts of common biochemical reactions, there are a few second messenger signaling systems such as the ubiquitous cyclic di-GMP second messenger system that arise through the synthesis of dedicated multidomain enzymes triggered by multiple diverse external and internal signals. Being one of the most numerous and widespread signaling system in bacteria, cyclic di-GMP signaling contributes to adjust physiological and metabolic responses in all available ecological niches. Those niches range from deep-sea and hydrothermal springs to the intracellular environment in human immune cells such as macrophages. This outmost adaptability is possible by the modularity of the cyclic di-GMP turnover proteins which enables coupling of enzymatic activity to the diversity of sensory domains and the flexibility in cyclic di-GMP binding sites. Nevertheless, commonly regulated fundamental microbial behavior include biofilm formation, motility, and acute and chronic virulence. The dedicated domains carrying out the enzymatic activity indicate an early evolutionary origin and diversification of "bona fide" second messengers such as cyclic di-GMP which is estimated to have been present in the last universal common ancestor of archaea and bacteria and maintained in the bacterial kingdom until today. This perspective article addresses aspects of our current view on the cyclic di-GMP signaling system and points to knowledge gaps that still await answers.