Bis-(3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) is a ubiquitous bacterial second-messenger molecule that is involved in the molecular decision between planktonic motile and sedentary bacterial 'lifestyles': that is, 'to swim or to stick'. In general, high c-di-GMP levels reduce the expression and/or activity of flagella and stimulate the expression of various adhesins and biofilm-associated exopolysaccharides (EPSs). In addition, c-di-GMP controls virulence of animal and plant pathogens and is involved in cell cycle control in certain bacteria.
c-di-GMP is synthesized by diguanylate cyclases (DGCs) and degraded by c-di-GMP phosphodiesterases (PDEs). DGC activity is provided by GGDEF domains and PDE activity is provided by either EAL or HD-GYP domains: the amino acid motifs after which they were named contribute to their respective enzymatic activities. Environmental and cellular signals control the expression and, through amino-terminal sensory domains, activities of DGCs and PDEs.
c-di-GMP functions by binding to, and allosterically affecting the activity of, effector components, which not only include different types of proteins, but also RNA that acts as a riboswitch.
c-di-GMP-binding effectors directly control diverse target processes, including transcription (if the effector is a transcription factor), transcriptional elongation or translation (if the effector is a riboswitch), regulated proteolysis and the activities of enzymes or complex cellular structures (for example, flagella or specific EPS synthesis and excretion machineries).
The multiplicity of DGCs, PDEs and c-di-GMP-binding effectors in many bacterial species allows a plethora of signals to be integrated. It also provides the basis for functional and spatial sequestration of some c-di-GMP control modules in separate pathways that can operate in parallel. Local operation requires direct macromolecular interactions between the 'cognate' DGCs, PDEs, effectors and targets that make up a specific c-di-GMP control module, and can involve dynamic localization to specific sites in the cell (for example, distinct cell poles).
Direct interactions between the components of specific c-di-GMP control modules seem to have allowed the evolution of systems with 'degenerate' GGDEF and EAL domain proteins that have 'given up' c-di-GMP metabolism, and rely on protein–protein interactions only. Nonetheless, these systems seem to remain 'evolutionarily trapped' in their old physiological context: that is, the control of motility and/or biofilm-related functions.
On the stage of bacterial signal transduction and regulation, bis-(3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) has long played the part of Sleeping Beauty. c-di-GMP was first described in 1987, but only recently was it recognized that the enzymes that 'make and break' it are not only ubiquitous in the bacterial world, but are found in many species in huge numbers. As a key player in the decision between the motile planktonic and sedentary biofilm-associated bacterial 'lifestyles', c-di-GMP binds to an unprecedented range of effector components and controls diverse targets, including transcription, the activities of enzymes and larger cellular structures. This Review focuses on emerging principles of c-di-GMP signalling using selected systems in different bacteria as examples.
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Ross, P. et al. Regulation of cellulose synthesis in Acetobacter xylinum by cyclic diguanylate. Nature 325, 279–281 (1987). The first report of c-di-GMP as an allosteric activator for an enzyme.
Tal, R. et al. Three cdg operons control cellular turnover of cyclic di-GMP in Acetobacter xylinum: genetic organization and occurrence of conserved domains in isoenzymes. J. Bacteriol. 180, 4416–4425 (1998).
Jenal, U. Cyclic di-guanosine-monophosphate comes of age: a novel secondary messenger involved in modulating cell surface structures in bacteria? Curr. Opin. Microbiol. 7, 185–191 (2004).
Jenal, U. & Malone, J. Mechanisms of cyclic-di-GMP signaling in bacteria. Annu. Rev. Genet. 40, 385–407 (2006). An excellent and comprehensive review on both the mechanisms and physiological context of c-di-GMP signalling.
Römling, U., Gomelsky, M. & Galperin, M. Y. C-di-GMP: the dawning of a novel bacterial signalling system. Mol. Microbiol. 57, 629–639 (2005).
Römling, U. & Amikam, D. Cyclic di-GMP as a second messenger. Curr. Opin. Microbiol. 9, 1–11 (2006).
Ryan, R. P., Fouhy, Y., Lucey, F. & Dow, J. M. Cyclic di-GMP signaling in bacteria: recent advances and new puzzles. J. Bacteriol. 188, 8327–8334 (2006).
Wolfe, A. J. & Visick, K. L. Get the message out: cyclic-di-GMP regulates multiple levels of flagellum-based motility. J. Bacteriol. 190, 463–475 (2008).
Cotter, P. A. & Stibitz, S. c-di-GMP-mediated regulation of virulence and biofilm formation. Curr. Opin. Microbiol. 10, 17–23 (2007).
Dow, J. M., Fouhy, Y., Lucey, J. F. & Ryan, R. P. The HD-GYP domain, cyclic di-GMP signaling, and bacterial virulence to plants. Mol. Plant Microbe Interact. 19, 1378–1384 (2006).
Ryan, R. P. et al. Cyclic di-GMP signalling in the virulence and environmental adaptation of Xanthomonas campestris. Mol. Microbiol. 63, 429–442 (2007).
Tamayo, R., Pratt, J. T. & Camilli, A. Roles of cyclic diguanylate in the regulation of bacterial pathogenesis. Annu. Rev. Microbiol. 61, 131–148 (2007).
Duerig, A. et al. Second messenger-mediated spatiotemporal control of protein degradation regulates bacterial cell cycle progression. Genes Dev. 23, 93–104 (2009). This paper not only reports the first GGDEF I site-type c-di-GMP effector protein, but also identifies the direct target — a cell cycle regulator that is targeted for proteolysis — thereby revealing that this process is essential for cell cycle progression in C. crescentus.
Fineran, P. C., Williamson, N. R., Lilley, K. S. & Salmond, G. P. Virulence and prodigiosin antibiotic biosynthesis in Serratia are regulated pleiotropically by the GGDEF/EAL domain protein, PigX. J. Bacteriol. 189, 7653–7662 (2007).
Hickman, J. W., Tifrea, D. F. & Harwood, C. S. A chemosensory system that regulates biofilm formation through modulation of cyclic diguanylate levels. Proc. Natl Acad. Sci. USA 102, 14422–14427 (2005).
Malone, J. et al. The structure–function relationship of WspR, a Pseudomonas fluorescens response regulator with a GGDEF output domain. Microbiology 153, 980–994 (2007).
Paul, R. et al. Cell cycle-dependent dynamic localization of a bacterial response regulator with a novel di-guanylate cyclase output domain. Genes Dev. 18, 715–727 (2004). The first experimental demonstration that the GGDEF domain exhibits DGC activity and that a DGC (PleD) is localized to a distinct cellular site (a cell pole) at a specific phase of the cell cycle of C. crescentus.
Ryjenkov, D. A., Tarutina, M., Moskvin, O. V. & Gomelsky, M. Cyclic diguanylate is a ubiquitous signaling molecule in bacteria: insights into biochemistry of the GGDEF protein domain. J. Bacteriol. 187, 1792–1798 (2005).
Chang, A. L. et al. Phosphodiesterase A1, a regulator of cellulose synthesis in Acetobacter xylinum, is a heme-based sensor. Biochemistry 40, 3420–3426 (2001).
Christen, M., Christen, B., Folcher, M., Schauerte, A. & Jenal, U. Identification and characterization of a cyclic di-GMP-specific phosphodiesterase and its allosteric control by GTP. J. Biol. Chem. 280, 30829–30837 (2005).
Schmidt, A. J., Ryjenkov, D. A. & Gomelsky, M. The ubiquitous protein domain EAL is a cyclic diguanylate-specific phosphodiesterase: enzymatically active and inactive EAL domains. J. Bacteriol. 187, 4774–4781 (2005).
Ryan, R. P. et al. Cell–cell signaling in Xanthomonas campestris involves an HD-GYP domain protein that functions in cyclic di-GMP turnover. Proc. Natl Acad. Sci. USA 103, 6712–6717 (2006). The first study to detect the PDE activity of an HD-GYP domain.
Tamayo, R., Tischler, A. D. & Camilli, A. The EAL domain protein VieA is a cyclic diguanylate phosphodiesterase. J. Biol. Chem. 280, 33324–33330 (2005).
Tschowri, N. & Hengge, R. The BLUF-EAL protein YcgF acts as a direct anti-repressor in a blue light response of E.coli. Genes Dev. 23, 522–534 (2009). This is the first paper to describe the direct molecular function of a degenerate EAL protein that depends on a protein–protein interaction for its activity.
Suzuki, K., Babitzke, P., Kushner, S. R. & Romeo, T. Identification of a novel regulatory protein (CsrD) that targets the global regulatory RNAs CsrB and CsrC for degradation by RNase E. Genes Dev. 20, 2605–2617 (2006).
Botsford, J. L. & Harman, J. G. Cyclic AMP in prokaryotes. Microbiol. Rev. 56, 100–122 (1992).
Holland, K., Busby, S. J. & Lloyd, G. S. New targets for the cyclic AMP receptor protein in the Escherichia coli K-12 genome. FEMS Microbiol. Lett. 274, 89–94 (2007).
Imamura, R. et al. Identification of the cpdA gene encoding cyclic 3′, 5′-adenosine monophosphate phosphodiesterase in Escherichia coli. J. Biol. Chem. 271, 25423–25429 (1996).
Chan, C. et al. Structural basis of activity and allosteric control of diguanylate cyclase. Proc. Natl Acad. Sci. USA 101, 17084–17089 (2004).
Paul, R. et al. Activation of the diguanylate cyclase PleD by phosphorylation-mediated dimerization. J. Biol. Chem. 282, 29170–29177 (2007).
Wassmann, P. et al. Structure of BeF3-modified response regulator PleD: implications of diguanylate cyclase activation, catalysis, and feedback inhibition. Structure (Camb.) 15, 915–927 (2007).
Christen, B. et al. Allosteric control of cyclic di-GMP signaling. J. Biol. Chem. 281, 32015–32024 (2006). The authors showed that most DGCs have a secondary binding site for c-di-GMP (the I site) that is involved in product feedback inhibition.
De, N. et al. Phosphorylation-independent regulation of the diguanylate cyclase WspR. PLoS Biol. 6, e67 (2008).
Rao, F., Yang, Y., Qi, Y. & Liang, Z. X. Catalytic mechanism of c-di-GMP specific phosphodiesterase: a study of the EAL domain-containing RocR from Pseudomonas aeruginosa. J. Bacteriol. 190, 3622–3631 (2008). This paper provides the structure of distinct conserved amino acids of an EAL domain and assigns them specific functions.
Galperin, M. Y., Natale, D. A., Aravind, L. & Koonin, E. V. A specialized version of the HD hydrolase domain implicated in signal transduction. J. Mol. Microbiol. Biotechnol. 1, 303–305 (1999).
García, B. et al. Role of the GGDEF protein family in Salmonella cellulose biosynthesis and biofilm formation. Mol. Microbiol. 54, 264–277 (2004).
Kuchma, S. L. et al. BifA, a cyclic-di-GMP phosphodiesterase, inversely regulates biofilm formation and swarming motility by Pseudomonas aeruginosa PA14. J. Bacteriol. 189, 8165–8178 (2007).
Weber, H., Pesavento, C., Possling, A., Tischendorf, G. & Hengge, R. Cyclic-di-GMP-mediated signaling within the σS network of Escherichia coli. Mol. Microbiol. 62, 1014–1034 (2006). This paper shows that a specific DGC–PDE pair (YdaM–YciR) is crucial for adhesive curli fimbriae formation in E. coli and is the first to link c-di-GMP signalling to the general stress response.
Tarutina, M., Ryjenkov, D. A. & Gomelsky, L. An unorthodox bacteriophytochrome from Rhodobacter sphaeroides involved in turnover of the second messenger c-di-GMP. J. Biol. Chem. 281, 34751–34758 (2006).
Ferreira, R. B. R., Antunes, L. C. M., Greenberg, E. P. & McCarter, L. L. Vibrio parahaemolyticus ScrC modulates cyclic dimeric GMP regulation of gene expression relevant to growth on surfaces. J. Bacteriol. 190, 851–860 (2008).
Kumar, M. & Chatterji, D. Cyclic-di-GMP: a second messenger required for long-term survival, but not for biofilm formation, in Mycobacterium smegmatis. Microbiology 154, 2942–2955 (2008).
Galperin, M. Y., Nikolskaya, A. N. & Koonin, E. V. Novel domains of the prokaryotic two-component signal transduction systems. FEMS Microbiol. Lett. 203, 11–21 (2001).
Galperin, M. Y. Bacterial signal transduction network in a genomic perspective. Environ. Microbiol. 6, 552–567 (2004).
Delgado-Nixon, V. M., Gonzalez, G. & Gilles-Gonzalez, M.-A. Dos, a heme-binding PAS protein from Escherichia coli, is a direct oxygen sensor. Biochemistry 39, 2685–2691 (2000).
Sasakura, Y. et al. Characterization of a direct oxygen sensor heme proein from Escherichia coli. Effects of the heme redox states and mutations at the heme-binding site on catalysis and structure. J. Biol. Chem. 277, 23821–23827 (2002).
Takahashi, H. & Shimizu, T. Phosphodiesterase activity of Ec DOS, a heme-regulated enzyme from Escherichia coli, toward 3′,5′-cyclic diguanylic acid is obviously enhanced by O2 and Co binding. Chem. Lett. 35, 970–971 (2006).
French, C. E., Bell, J. M. & Ward, F. B. Diversity and distribution of hemerythrin-like proteins in prokaryotes. FEMS Microbiol. Lett. 279, 131–145 (2008).
Hasegawa, K., Masuda, S. & Ono, T. A. Light induced structural changes of a full-length protein and its BLUF domain in YcgF (Blrp), a blue-light sensing protein that uses FAD (BLUF). Biochemistry 45, 3785–3793 (2006).
Nakasone, Y., Ono, T. A., Ishii, A., Masuda, S. & Terazima, M. Transient dimerization and conformational change of a BLUF protein: YcgF. J. Am. Chem. Soc. 129, 7028–7035 (2007).
Hurley, J. H. GAF domains: cyclic nucleotides come full circle. Sci. STKE 164, pe1 (2003).
Martinez-Wilson, H. F., Tamayo, R., Tischler, A. D., Lazinski, D. W. & Camilli, A. The Vibrio cholerae hybrid sensor kinase VieS contributes to motility and biofilm regulation by altering cyclic diguanylate level. J. Bacteriol. 190, 6439–6447 (2008).
Güvener, Z. T. & Harwood, C. S. Subcellular location characteristics of the Pseudomonas aeruginosa GGDEF protein, WspR, indicate that it produces cyclic-di-GMP in response to growth on surfaces. Mol. Microbiol. 66, 1459–1473 (2007).
Kazmierczak, B. I., Lebron, M. B. & Murray, T. S. Analysis of FimX, a phosphodiesterase that governs twitching motility in Pseudomonas aeruginosa. Mol. Microbiol. 60, 1026–1043 (2006).
Amikam, D. & Galperin, M. Y. PilZ domain is part of the bacterial c-di-GMP binding protein. Bioinformatics 22, 3–6 (2006). An insightful bioinformatic prediction of c-di-GMP-binding activity by PilZ domain proteins.
Merighi, M., Lee, V. T., Hyodo, M., Hayakawa, Y. & Lory, S. The second messenger bis-(3′-5′)-cyclic-GMP and its PilZ domain-containing receptor Alg44 are required for alginate biosynthesis in Pseudomonas aeruginosa. Mol. Microbiol. 65, 876–895 (2007).
Oglesby, L., Jain, S. & Ohman, D. E. Membrane topology and roles of Pseudomonas aeruginosa Alg8 and Alg44 in alginate polymerization. Microbiology 154, 1605–1615 (2008).
Benach, J. et al. The structural basis of cyclic diguanylate signal transduction by PilZ domains. EMBO J. 26, 5153–5166 (2007).
Hickman, J. W. & Harwood, C. S. Identification of FleQ from Pseudomonas aeruginosa as a c-di-GMP-responsive transcription factor. Mol. Microbiol. 69, 376–389 (2008).
Lee, V. T. et al. A cyclic-di-GMP receptor required for bacterial exopolysaccharide production. Mol. Microbiol. 65, 1474–1484 (2007).
Beyhan, S., Odell, L. S. & Yildiz, F. H. Identification and characterization of cyclic diguanylate signaling systems controlling rugosity in Vibrio cholerae. J. Bacteriol. 190, 7392–7405 (2008).
Sudarsan, N. et al. Riboswitches in eubacteria sense the second messenger cyclic di-GMP. Science 321, 411–413 (2008). Identification in several species of a c-di-GMP-binding riboswitch that serves as a direct effector for the regulation by c-di-GMP in 5′-untranslated regions of mRNAs.
Beyhan, S. & Yildiz, F. H. Smooth to rugose phase variation in Vibrio cholerae can be mediated by a single nucleotide change that targets c-di-GMP signalling pathway. Mol. Microbiol. 63, 995–1007 (2007).
Kader, A., Simm, R., Gerstel, U., Morr, M. & Römling, U. Hierarchical involvement of various GGDEF domain proteins in rdar morphotype development of Salmonella enterica serovar typhimurium. Mol. Microbiol. 60, 602–616 (2006).
Simm, R., Morr, M., Kader, A., Nimtz, M. & Römling, U. GGDEF and EAL domains inversely regulate cyclic di-GMP levels and transition from sessility to motility. Mol. Microbiol. 53, 1123–1134 (2004).
Tischler, A. D. & Camilli, A. Cyclic diguanylate regulates Vibrio cholerae virulence gene expression. Infect. Immun. 73, 5873–5882 (2005). A key paper that links c-di-GMP signalling to virulence gene regulation.
Weinhouse, H. et al. c-di-GMP-binding protein, a new factor regulating cellulose synthesis in Acetobacter xylinum. FEBS Lett. 416, 207–211 (1997).
Christen, M. et al. DgrA is a member of a new family of cyclic diguanosine monophosphate receptors and controls flagellar motor function in Caulobacter crescentus. Proc. Natl Acad. Sci. USA 104, 4112–4117 (2007).
Pratt, J. T., Tamayo, R., Tischler, A. D. & Camilli, A. PilZ domain proteins bind cyclic diguanylate and regulate diverse processes in Vibrio cholerae. J. Biol. Chem. 282, 12860–12870 (2007).
Ryjenkov, D. A., Simm, R., Römling, U. & Gomelsky, M. The PilZ domain is a receptor for the second messenger c-di-GMP: the PilZ protein YcgR controls motility in enterobacteria. J. Biol. Chem. 281, 30310–30314 (2006).
Pesavento, C. et al. Inverse regulatory coordination of motility and curli-mediated adhesion in Escherichia coli. Genes Dev. 22, 2434–2446 (2008). This paper clarifies the molecular functioning of the complex switch mechanism that results in mutual exclusion of the FlhDC (motility) and σS (adhesion) transcriptional control cascades.
Simm, R., Lusch, A., Kader, A., Andersson, M. & Römling, U. Role of EAL-containing proteins in multicellular behavior of Salmonella enterica serovar typhimurium. J. Bacteriol. 189, 3613–3623 (2007).
Brown, P. K. et al. MlrA, a novel regulator of curli (Agf) and extracellular matrix synthesis by Escherichia coli and Salmonella enterica serovar typhimurium. Mol. Microbiol. 41, 349–363 (2001).
Gerstel, U., Park, C. & Römling, U. Complex regulation of csgD promoter activity by global regulatory proteins. Mol. Microbiol. 49, 639–654 (2003).
Jubelin, G. et al. CpxR/OmpR interplay regulates curli gene expression in response to osmolarity in Escherichia coli. J. Bacteriol. 187, 2038–2049 (2005).
Prigent-Combaret, C. et al. Complex regulatory network controls initial adhesion and biofilm formation in Escherichia coli via regulation of the csgD gene. J. Bacteriol. 2001, 7213–7223 (2001).
Vianney, A. et al. Escherichia coli tol and rcs genes participate in the complex network affecting curli synthesis. Microbiology 151, 2487–2497 (2005).
Hammer, B. K. & Bassler, B. L. Distinct sensory pathways in Vibrio cholerae El Tor and classical biotypes modulated c-di-GMP levels to control biofilm formation. J. Bacteriol. 191, 169–177 (2008).
Lim, B., Beyhan, S. & Yildiz, F. H. Regulation of Vibrio polysaccharide synthesis and virulence factor production by CdgC, a GGDEF-EAL domain protein, in Vibrio cholerae. J. Bacteriol. 189, 717–729 (2007).
Waters, C. M., Lu, W., Rabinowitz, J. D. & Bassler, B. L. Quorum sensing controls biofilm formation in Vibrio cholerae through modulation of cyclic di-GMP levels and repression of vpsT. J. Bacteriol. 190, 2527–2536 (2008).
Girgis, H. S., Liu, Y., Ryu, W. S. & Tavazoie, S. A comprehensive genetic characterization of bacterial motility. PLoS Genet. 3, e154 (2007). Using novel techniques for genome-wide genetic analysis, 36 novel genes that are associated with motility, including genes involved in c-di-GMP control of motility, were identified and analysed.
Paul, R. et al. Allosteric regulation of histidine kinases by their cognate response regulator determines cell fate. Cell 133, 452–461 (2008).
Galperin, M. Y. A census of membrane-bound and intracellular signal transduction proteins in bacteria: bacterial IQ, extroverts and introverts. BMC Microbiol. 5, 35 (2005).
Buckstein, M. H., He, J. & Rubin, H. Characterization of nucleotide pools as a function of physiological state in Escherichia coli. J. Bacteriol. 190, 718–726 (2008).
Sommerfeldt, N. et al. Gene expression patterns and differential input into curli fimbriae regulation of all GGDEF/EAL domain proteins in Escherichia coli. Microbiology 155, 1318–1331 (2009).
Frye, J. et al. Identification of new flagellar genes of Salmonella enterica serovar typhimurium. J. Bacteriol. 188, 2233–2243 (2006).
Römling, U., Sierralta, W. D., Eriksson, K. & Normark, S. Multicellular and aggregative behaviour of Salmonella typhimurum strains is controlled by mutations in the agfD promoter. Mol. Microbiol. 28, 249–264 (1998).
Jonas, K. et al. The RNA binding protein CsrA controls c-di-GMP metabolism by directly regulating the expression of GGDEF proteins. Mol. Microbiol. 70, 236–257 (2008).
Babitzke, P. & Romeo, T. CsrB sRNA family: sequestration of RNA-binding regulatory proteins. Curr. Opin. Microbiol. 10, 156–163 (2007).
Wang, X. et al. CsrA post-transcriptionally represses pgaABCD, responsible for synthesis of a biofilm polysaccharide adhesin of Escherichia coli. Mol. Microbiol. 56, 1648–1663 (2005).
Fong, J. C. N. & Yildiz, F. H. Interplay between cAMP–CRP and c-di-GMP in Vibrio cholerae biofilm formation. J. Bacteriol. 190, 6646–6659 (2008).
Yildiz, F. H., Liu, X. S., Heydorn, A. & Schoolnick, G. K. Molecular analysis of rugosity in a Vibrio cholerae O1 El Tor phase variant. Mol. Microbiol. 53, 497–515 (2004).
Camilli, A. & Bassler, B. L. Bacterial small-molecule signaling pathways. Science 311, 1113–1116 (2006).
Schild, S. et al. Genes induced late in infection increase fitness of Vibrio cholerae after release into the environment. Cell Host Microbe 2, 264–277 (2007).
Tamayo, R., Schild, S., Pratt, J. T. & Camilli, A. Role of cyclic di-GMP during El Tor biotype Vibrio cholerae infection: characterization of the in vivo-induced cyclic di-GMP phosphodiesterase CdpA. Infect. Immun. 76, 1617–1627 (2008).
Kirillina, O., Fetherstone, J. D., Bobrov, A. G., Abney, J. & Perry, R. D. HmsP, a putative phosphodiesterase, and HmsT, a putative diguanylate cyclase, control Hms-dependent biofilm formation in Yersinia pestis. Mol. Microbiol. 54, 75–88 (2004).
Perry, R. D. et al. Temperature regulation of the hemin storage (Hms+) phenotype of Yersinia pestis is posttranscriptional. J. Bacteriol. 186, 1638–1647 (2004). The first report to show that regulated proteolysis of GGDEF proteins plays a key part in c-di-GMP signalling.
Kulasakara, H. et al. Analysis of Pseudomonas aeruginosa diguanylate cyclases and phosphodiesterase reveals a role for bis-(3′-5′)-cyclic-GMP in virulence. Proc. Natl Acad. Sci. USA 103, 2839–2844 (2006).
Baker, D. A. & Kelly, J. M. Structure, function and evolution of microbial adenylyl and guanylyl cyclases. Mol. Microbiol. 52, 1229–1242 (2004).
Shenoy, A. R. & Visweswariah, S. S. Class III nucleotide cyclases in bacteria and archaebacteria: lineage-specific expansion of adenylyl cyclases and a dearth of guanylyl cyclases. FEBS Lett. 561, 11–21 (2004).
Shenoy, A. R. & Visweswariah, S. S. New messages from old messengers: cAMP and mycobacteria. Trends Microbiol. 14, 543–550 (2006).
Willoughby, D. & Cooper, D. M. Organization and Ca2+ regulation of adenylyl cyclases in cAMP microdomains. Physiol. Rev. 87, 965–1010 (2007).
Andrade, M. O. et al. The HD-GYP domain of RpfG mediates a direct linkage between the Rpf quorum-sensing pathway and a subset of diguanylate cyclase proteins in the phytopathogen Xanthomonas axonopodis pv citri. Mol. Microbiol. 62, 537–551 (2006).
Bobrov, A. G., Kirillina, O., Forman, S., Mack, D. & Perry, R. D. Insights into Yersinia pestis biofilm development: topology and co-interaction of Hms inner membrane proteins involved in exopolysaccharide production. Environ. Microbiol. 10, 1419–1432 (2008).
Huitema, E., Pritchard, S., Matteson, D., Radhakrishnan, S. K. & Viollier, P. H. Bacterial birth scar proteins mark future flagellum assembly site. Cell 124, 1025–1037 (2006). This paper describes the striking finding that marker proteins (TipN and TipF) are deposited at the new-born poles during cell division. One of these proteins was shown to be an EAL-type PDE that was essential for flagellum assembly at the incipient swarmer pole of C. crescentus.
Jonas, K., Tomenius, H., Römling, U., Georgellis, D. & Melefors, O. Identification of YhdA as a regulator of the Escherichia coli carbon storage regulation system. FEMS Microbiol. Lett. 264, 232–237 (2006).
Holland, L. M. et al. A staphylococcal GGDEF domain protein regulates biofilm formation independently of c-di-GMP. J. Bacteriol. 190, 5178–5189 (2008).
Thormann, K. M. et al. Control of formation and cellular detachment from Shewanella oneidensis MR-1 biofilms by cyclic di-GMP. J. Bacteriol. 188, 2681–2691 (2006).
Adler, J. & Templeton, B. The effect of environmental conditions on the motility of Escherichia coli. J. Gen. Microbiol. 46, 175–184 (1967).
Amsler, C. D., Cho, M. & Matsumura, P. Multiple factors underlying the maximum motility of Escherichia coli as cultures enter post-exponential growth. J. Bacteriol. 175, 6238–6244 (1993).
Olsén, A., Wick, M. J., Mörgelin, M. & Björck, L. Curli, fibrous surface proteins of Escherichia coli interact with major histocompatibility complex class I molecules. Infect. Immun. 66, 944–949 (1998).
Brombacher, E., Baratto, A., Dorel, C. & Landini, P. Gene expression regulation by the curli activtor CsgD protein: modulation of cellulose biosynthesis and control of negative determinants for microbial adhesion. J. Bacteriol. 188, 2027–2037 (2006).
Zogaj, X., Nimtz, M., Rohde, M., Bokranz, W. & Römling, U. The multicellular morphotypes of Salmonella typhimurium and Escherichia coli produce cellulose as the second component of the extracellular matrix. Mol. Microbiol. 39, 1452–1463 (2001). The first report of cellulose as an extracellular matrix polysaccharide in biofilms at a wet surface–air interface.
Aldridge, P., Paul, R., Goymer, P., Rainey, P. & Jenal, U. Role of the GGDEF regulator PleD in polar development of Caulobacter crescentus. Mol. Microbiol. 47, 1695–1708 (2003).
Viollier, P. H., Sternheim, N. & Shapiro, L. Identification of a localization factor for the polar positioning of bacterial structural and regulatory proteins. Proc. Natl Acad. Sci. USA 99, 13831–13836 (2002).
Alm, R. A., Bodero, A. J., Free, P. D. & Mattick, J. S. Identification of a novel gene, pilZ, essential for type 4 fimbrial biogenesis in Pseudomonas aeruginosa. J. Bacteriol. 178, 46–53 (1996).
The author thanks U. Jenal for providing the figure in BOX 2 and for helpful discussions, and C. Pesavento for providing input on the manuscript. Work from the author's laboratory cited in this review has been supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie and the Dr Hans Messner Stiftung.
The author declares no competing financial interests.
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Hengge, R. Principles of c-di-GMP signalling in bacteria. Nat Rev Microbiol 7, 263–273 (2009). https://doi.org/10.1038/nrmicro2109
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