Second Messenger Proteins

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 Second Messenger Proteins Background

Microorganisms need to cope with variations of the external environment and rely on signaling molecules to translate these changes into intracellular responses and to adapt to the new condition. After cells sense an external stimulus (i.e., first messenger), a second messenger will be synthesized or degraded to rapidly amplify the first messenger signal and initiate physiological changes. Proteins involved in the synthesis and degradation of second messengers are generally constitutively present in the cell to support rapid activation. First messenger induced fluctuations of second messengers are propagated in cells through binding to DNA, RNA, or proteins/protein complexes. The ligand-effector complex will then trigger a signal cascade involving specific receptors, outputs and feedback processes. This signal cascade is common for all known second messengers.

There is a rich variation of second messengers in prokaryotic organisms, from cyclic nucleotides to gases. In cyanobacteria, the most intensely studied second messengers are calcium (Ca2+), guanosine tetraphosphate or pentaphosphate (ppGpp or pppGpp; hereafter (p)ppGpp), and cyclic adenosine 3′,5′-monophosphate (cAMP). Lesser studied second messengers in cyanobacteria are cyclic dimeric GMP (c-di-GMP), cyclic guanosine 3′,5′-monophosphate (cGMP) and nitric oxide (NO). Finally, cyclic dimeric AMP (c-di-AMP) remains to be characterized in cyanobacteria. All of these second messengers are commonly studied in pathogenic bacteria.

Calcium has been considered for its ability to influence cell structure and differentiation, motility, and gene expression in pathogenic bacteria. The molecule (p)ppGpp is mainly studied in these bacteria for is involvement under cell starvation stress. Cyclic AMP has been implicated in sugar metabolism, motility and virulence in pathogenic bacterial systems. Cyclic di-GMP impacts several processes in bacterial cells including transcription, RNA turnover, biofilm formation, protein synthesis, motility, and virulence. NO serves as an important factor in host-pathogen interactions. Finally, the most recently discovered nucleotide second messengers are c-di-AMP, which impacts ion transport, membrane lipid homeostasis, DNA integrity, and cGMP, which has been implicated in the control of cyst formation.

Cyclic adenosine 3’,5’-monophosphate (cAMP) was first identified as a second messenger in liver cells in 1957 by Earl Sutherland, and as a signaling molecule regulating carbon metabolism in Escherichia coli in 1969. In bacteria, intracellular cAMP levels are heavily influenced by the availability of extracellular nutrient sources, and cAMP along with cAMP Receptor Protein (CRP) govern the utilization of nutrient sources. Cyclic guanosine 3’,5’-monophosphate (cGMP) was first identified in 1963 in rat urine and levels correlated with the hormonal state in the animal. A role for cGMP is largely restricted to eukaryotic cells, where it is associated with transmembrane signal transduction, protein kinase activity and many other important processes. In bacteria, production of cGMP was observed as early as 1974, but only recently has a function for cGMP in intracellular signaling been ascribed. In studies using Rhodospirillum centenum, a cGMP specific synthase was identified and cGMP production was linked to cyst formation. The linear nucleotides guanosine 3’,5’-bispyrophosphate (ppGpp) and guanosine 3’-diphosphate, 5’-triphosphate (pppGpp) are also intracellular bacterial second messengers. (p)ppGpp production in E. coli was first identified in 1970 and later classified as an “alarmone” produced in response to nutrient starvation and other stresses.

It was not until several decades following the discovery of cAMP, cGMP and (p)ppGpp that cyclic dinucleotides were identified. Perhaps the most broadly studied is cyclic dimeric guanosine 3’,5’-monophosphate (c-di-GMP), identified in 1989 as an allosteric regulator of bacterial cellulose synthase in Gluconacetobacter xylinum. The increased interest in c-di-GMP as a ubiquitous bacterial second messenger in the last decade, led to the identification of its role in virulence, motility, and biofilm formation in a vast number of organisms. About 20 years later, in 2008, cyclic dimeric adenosine 3’,5’- monophosphate (c-di-AMP) was identified as second messenger in Gram-positive bacteria. Since the discovery of c-di-AMP, studies have shown that it regulates bacterial cell growth, sporulation, stress responses, antimicrobial resistance and virulence. Lastly, cyclic guanosine monophosphate adenosine monophospate (cGMP-AMP) was identified in 2012. A function for c-GMP-AMP has been ascribed to few organisms; in V. cholerae c-GMP-AMP production during infection promotes chemotaxis and in numerous Deltaproteobacteria, including Geobacter species, it is predicted to function in extracellular electron transfer.