Sensing the messenger: the diverse ways that bacteria signal through c-di-GMP

Protein Sci. 2012 Jul;21(7):929-48. doi: 10.1002/pro.2093. Epub 2012 Jun 5.


An intracellular second messenger unique to bacteria, c-di-GMP, has gained appreciation as a key player in adaptation and virulence strategies, such as biofilm formation, persistence, and cytotoxicity. Diguanylate cyclases containing GGDEF domains and phosphodiesterases containing either EAL or HD-GYP domains have been identified as the enzymes controlling intracellular c-di-GMP levels, yet little is known regarding signal transmission and the sensory targets for this signaling molecule. Although limited in number, identified c-di-GMP receptors in bacteria are characterized by prominent diversity and multilevel impact. In addition, c-di-GMP has been shown to have immunomodulatory effects in mammals and several eukaryotic c-di-GMP sensors have been proposed. The structural biology of c-di-GMP receptors is a rapidly developing field of research, which holds promise for the development of novel therapeutics against bacterial infections. In this review, we highlight recent advances in identifying bacterial and eukaryotic c-di-GMP signaling mechanisms and emphasize the need for mechanistic structure-function studies on confirmed signaling targets.

Publication types

  • Review

MeSH terms

  • Bacteria / chemistry
  • Bacteria / metabolism*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / metabolism
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / metabolism
  • Models, Molecular
  • Phosphoric Diester Hydrolases / chemistry
  • Phosphoric Diester Hydrolases / metabolism
  • Phosphorus-Oxygen Lyases / chemistry
  • Phosphorus-Oxygen Lyases / metabolism
  • Protein Conformation
  • Signal Transduction*


  • Bacterial Proteins
  • Escherichia coli Proteins
  • bis(3',5')-cyclic diguanylic acid
  • Phosphoric Diester Hydrolases
  • Phosphorus-Oxygen Lyases
  • diguanylate cyclase
  • Cyclic GMP