cAMP, c-di-GMP, c-di-AMP and now cGMP: Bacteria use them all!

By Mark Gomelsky. 2011

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Cyclic nucleotide second messengers represent a cornerstone signal transduction mechanism in all domains of life. Cyclic adenosine 3′,5′-monophosphate (cAMP) and cyclic guanosine 3′,5′-monophosphate (cGMP) are the most important nucleotide messengers in eukaryotes. For several decades, bacteria have been known to use cAMP to control a variety of processes, from utilization of alternative sugars to motility and virulence. However, until now, the involvement of cGMP in bacterial signalling has been at best controversial (reviewed in Linder, 2010). This controversy is now over. Carl Bauer from Indiana University and his colleagues in this issue of Molecular Microbiology provide unambiguous evidence that the Alphaproteobacterium Rhodospirillum centenum synthesizes cGMP and uses it for regulation of a developmental process via the cGMP-dependent transcription factor. Among nucleotide messengers, cGMP represented the last bastion of eukaryotic exclusivity; and that bastion has now fallen. Over the last few years, the universe of bacterial cyclic nucleotide messengers has been rapidly expanding (Fig. 1). A few years ago, a new cyclic nucleotide (more precisely, cyclic dinucleotide), cyclic dimeric GMP (c-diGMP) discovered in Moshe Benziman’s lab at the Hebrew University of Jerusalem in the mid-1980s (Ross et al., 1987), rose from obscurity to the limelight of a ubiquitous second messenger (Ryjenkov et al., 2005). c-di-GMP is now known to control a transition in the Proteobacteria from a single-cell motile state to a surface-attached multicellular state. In the multicellular state, c-di-GMP plays a central role in formation and dissolution of biofilms by regulating – via diverse mechanisms – production of extracellular polysaccharides, adhesive proteins, pili and flagella (Wolfe and Visick, 2009). In 2008, we have learned from Karl-Peter Hopfner’s group at Ludwig Maximilians University in Munich about yet another cyclic dinucleotide, c-di-AMP. At present little is known about c-di-AMP (Fig. 1), except that it is involved in DNA damage-dependent cell cycle control in Bacillus subtilis (Witte et al., 2008) and that it is essential for viability of the food-borne pathogen Listeria monocytogenes (Woodward et al., 2010). However, based on the broad distribution of diadenylyl cyclases in Bacteria and Archaea, it is clear that c-di-AMP is poised to join its fellow cyclic nucleotide messengers as a ubiquitous and important signalling molecule (Römling, 2008). While in eukaryotes the role of cGMP in signal transduction can hardly be overestimated, the involvement of this molecule in bacterial regulation has been murky. Early on, the bacterial cGMP-signalling field has had several false starts. For instance, intracellular cGMP levels in Escherichia coli and Bacillus lichenijormis (Bernlohr et al., 1976) were estimated to be approximately two orders of magnitude lower than levels of known second messengers like cAMP and c-di-GMP, and some reports linking cGMP to physiological functions (Black et al., 1980) proved to be irreproducible. To my knowledge, there is no credible evidence that E. coli or Bacillus involve cGMP in signalling. However, evidence has been accumulating that some ‘bugs’ might do so. For example, biologically relevant levels of cGMP have been measured in the cyanobacterium Synechocystis sp. PCC6803, and these levels change in response to environmental conditions (Cadoret et al., 2005). Furthermore, the catalytic domain of the Synechocystis nucleotidyl cyclase, Cya2, has higher specific activity for synthesizing cGMP than cAMP (Rauch et al., 2008). Interestingly, Cya2 as well as all eukaryotic guanylyl cyclases are closely related to type III adenylyl cyclases, and, in fact, mutations in just a few residues can change substrate specificities in these cyclases (Sunahara et al., 1998; Ryu et al., 2010). Given this, why has evolution not changed these residues in bacterial adenylyl cyclases, and why have bacteria not exploited cGMP to diversify their signalling repertoire? The answer from the Marden and colleagues’ work is that we were simply not looking thoroughly enough. For the first time, Accepted 12 December, 2010. *For correspondence. E-mail gomelsky@uwyo.edu; Tel. (+1) 307 766 3522; Fax (+1) 307 766 3875. Molecular Microbiology (2011) 79(3), 562–565 doi:10.1111/j.1365-2958.2010.07514.x First published online 5 January 2011

Subfields: Biochemistry, Genetics, Molecular Biology

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