Another future challenge will be the adoption of our current knowledge about bacterial signal transduction to other disciplines, including medicine, health care, biotechnology and industry.
As hospital acquired multi-drug resistant bacteria emerge and spread to assume threatening proportions [240], a detailed knowledge about signalling systems is required for the development of novel antimicrobial drugs. Over the past years, different components of signal transduction systems have been discussed as potential drug targets. For example, the inhibition of two-component systems has attracted considerable attention, as they are highly abundant in bacteria and play an important role in the adaptation to bacterial stress, and often in pathogenesis [241-243]. Targeting the histidine kinases of two-component systems and the subsequent regulation of gene expression might allow the development of antibiotics with a new mode of action.
Also, the central roles of sRNA regulators in cellular physiology make them to attractive tools to combat bacterial spread. As interference with the functions of some of the sRNAs is detrimental to growth and several sRNAs contribute to virulence, these regulators and their interacting proteins have been considered as potential targets for antibacterial therapies [244]. In addition, the c-di-GMP signalling network has recently been recognized as a target to control infectious diseases and biofilms that cause serious problems in medicine and industry [245].
The understanding of the principles of bacterial signalling systems is also required for the attempt to engineer novel signal transduction systems that fulfil desired functions.
By dissecting and subsequently rationally “rewiring” signalling pathways it might be possible in the future to construct synthetic signalling pathways in vivo. As an example, reprogramming a two-component histidine kinase to activate the response regulator with a chemotaxis output domain could be useful to force bacteria to swim towards a particular chemical stimulus [246]. The bacteria could then be further engineered to execute a specific task once they arrive at the region of interest. The capability to engineer such synthetic bacterial networks would not only dramatically improve our ability to control bacterial spread, but would also allow the maximum exploitation of the beneficial behaviours of bacteria in biotechnological settings. For example, the inherent biosynthetic abilities of certain bacteria could be utilized for the large-scale production of biofuels (e.g. ethanol, butanol or hydrogen) or biopolymers (e.g.
cellulose, xanthan, bioplastics) [247]. Eventually, it might also be possible to harness the ability of bacteria to use oil, radioactive materials, or other contaminants as nutrient sources, thus adopting them as a cheap and ecological force to clean up polluted or contaminated environments [247].
The study of bacterial signalling network has during the recent years also emerged as a model for systems biology [247]. As bacteria are comparatively “simple” and tractable they provide an excellent basis to expand our understanding of how signalling network can control cellular behaviour in higher organisms. Eventually, this could lead to a better understanding and to an effective treatment of human diseases, which are caused by the failure of complex signalling networks, including different kinds of cancer or various autoimmune diseases.
8 EXECUTIVE SUMMARY
Introduction
The ability to process information depends on complex signalling networks, which control genes required to cope with certain environmental conditions.
Bacterial signalling networks consist of a number of modules, including two/one-component systems, ECF-systems, global regulator proteins and sRNAs as well as second messenger molecules.
The BarA-UvrY-Csr signalling system in E. coli and Salmonella was used as a model and consists of the global regulator CsrA, the sRNAs CsrB and CsrC, the BarA-UvrY (BarA-SirA) TCS and CsrD.
Major findings
YhdA (CsrD), a protein with degenerate GGDEF/EAL domains, regulates expression of the CsrB and CsrC sRNAs.
CsrA controls directly and indirectly the expression of GGDEF/EAL domain proteins and, thereby, links Csr with c-di-GMP signalling.
The CsrA-regulated genes ycdT and ydeH in E. coli encode diguanylate cyclases with functions in motility.
CsrA controls in S. Typhimurium GGDEF/EAL domain proteins that are different from the CsrA-regulated ones in E. coli.
CsrA negatively autoregulates its activity through CsrD.
pH 5 prevents BarA-UvrY mediated activation of csrB and csrC transcription.
csrB and csrC expression is greatly induced in nutrient poor medium, and is repressed by the addition of amino acids or rich medium.
Major conclusions
CsrA mediates its global effects by controlling c-di-GMP metabolism.
CsrA controls motility/virulence and biofilm phenotypes in an inverse manner.
CsrA couples carbon metabolism with the control of bacterial physiology.
The Csr system is controlled by the nutrient availability, allowing the adaptation to changing conditions, e.g. growth in the environment vs. survival in the host.
Global regulators combine c-di-GMP dependent and direct pathways within complex feedforward arrangements to regulate physiological processes.
The tight regulation of c-di-GMP metabolizing enzymes may allow specificity.
Regulation of c-di-GMP signalling occurs at multiple levels and is variable.
Unorthodox GGDEF-EAL domain protein, inactive in the synthesis or break down of c-di-GMP, can have regulatory functions in the c-di-GMP network.
9 ACKNOWLEDGEMENTS
A lot of people supported me during my PhD studies and made my time in Stockholm unforgettable. In particular, I would like to thank …
… my supervisor Öjar Melefors. You guided me through all the ups and downs during this work and helped me to become an independent researcher. You taught me how to develop my own ideas, how to go the long, troublesome way through the projects and how to get results published – without losing nerves. Thanks for always encouraging me, for providing me with everything I needed and for generously allowing me to travel to all conferences, courses or retreats I wanted. I wish you and your family all the best for the future!
… my co-supervisor Ute Römling. Thanks for all your scientific input, for your countless suggestions, your valuable comments on my manuscripts, and above all, for sharing the enthusiasm for a small chemical structure, c-di-GMP.
... Staffan Normark and Birgitta Henriques Normark for your suggestions and great inspirations, for our joint collaborations and for inviting me to numerous lab retreats, conferences, seminars, and glögg afternoons.
... Tony Romeo and Adrianne Edwards from the University of Florida and the Emory University School of Medicine in Atlanta for a very efficient and fruitful collaboration on the CsrA/c-di-GMP projects. I am still impressed by your beautiful gel-shifts, Adrianne!
... all other people I had the pleasure to collaborate and to publish with: Dimitris Georgellis and co-workers, Lyubov Belova, Henrik Tomenius, Roger Simm, Agaristi Lamprokostopoulou, Irfan Ahmad, Abdul Kader, Aaron Nelson, Stefan Fälker, Eva Morfeldt, Kjell Hultenby, Johannes Ries and Jan-Ingmar Flock.
... Lars Engstrand, the Head of the Department of Bacteriology at SMI, Ragnar Norrby, Director General of SMI, Marie Arsenian-Henriksson and Mats Wahlgren, the present and the former Head of MTC, for providing an excellent work environment.
... the foundations that financially supported this work, in particular the European Union that provided me with a Marie Curie Early Stage Research Training Fellowship (Sixth Framework Program, MEST-CT-2004-8475).
... all my colleagues who shared the everyday life at SMI. In particular many thanks to:
our former group members Henrik (who introduced me to the BarA-UvrY system) and Julija, my students Karin and Karina, my present and former office-mates Alma, Lech, Jolanta, Kim, Henrik, Melles, Lasse B., Anna T., the members from the Lars Engstrand group (especially many thanks for inviting me to all your social activities, including the fabulous skiing trip to Idre, wine tasting etc.), the members from the Birgitta Normark group (especially to Sandra, Stefan, Sofia, Christel, Marie, Sarah, Kathi and Florian for always having time for a chat between the corridors and for great fun on all the different conferences), Britt-Marie Hoffman and Anita Ekner for being excellent coordinators and all people sharing the fika rum på plan 2 with me for all the interesting and stimulating lunch discussions about all sorts of things!
... all the people outside of SMI, who greatly influenced my time as a PhD student:
the students and supervisors from the IMO-train group, the study coordinators Lena Norenius and Anna Lögdberg at MTC, the members of the Ute Römling group (especially to Claudia, Kathi, Agaristi, Uwe, Roger and Nina for nice conversations and all your help with strains, the camera, the HPLC or MALDI), my mentor Katrin Pütsep, for nice lunches and long discussions about life in and outside research, the members of the Agneta Richter-Dahlfors group (especially to Jorrit, Keira, Kalle, Karin and Peter, it was always great to see you at all the retreats, conferences and pubs), Jörg Vogel for helpful discussions and strains, John Kirby, Anca Segall, Susan Lovett and the rest of the ABG course for great and intense (!) four weeks in Cold Spring Harbor, and all the organizers of other courses and conferences that greatly influenced my research career.
... all my friends, in and outside KI, former and present “Foggies“, who made the past four years to a wonderful time: Sönke, Tina, Matteo, Laura, Florian, Sven, Julia, Hanna, Hervé, Therese, Stefan, Ollie, Joana, Claudia, Pedro, Anne-Marie, Lasse, Martin, Maria, Jens, Heather, Aurelie, Alison, Darja, Astrid, Anneke, Ursina, Eva, Ilaria, …
... my family, for always supporting me in everything I do.
... and, most importantly, Christian, for having gone through all of this with me together! Thank you for always being there for me!
10 REFERENCES
1. Rappe MS, Giovannoni SJ: The uncultured microbial majority. Annu Rev Microbiol 2003, 57:369-394.
2. Whitman WB, Coleman DC, Wiebe WJ: Prokaryotes: the unseen majority.
Proc Natl Acad Sci U S A 1998, 95(12):6578-6583.
3. Wolanin PM, Thomason PA, Stock JB: Histidine protein kinases: key signal transducers outside the animal kingdom. Genome Biol 2002, 3(10):REVIEWS3013.
4. Whitworth DE, Cock PJ: Two-component systems of the myxobacteria:
structure, diversity and evolutionary relationships. Microbiology 2008, 154(Pt 2):360-372.
5. Mizuno T: Compilation of all genes encoding two-component phosphotransfer signal transducers in the genome of Escherichia coli. DNA Res 1997, 4(2):161-168.
6. Galperin MY: A census of membrane-bound and intracellular signal transduction proteins in bacteria: bacterial IQ, extroverts and introverts.
BMC Microbiol 2005, 5:35.
7. Hoch JA: Two-component and phosphorelay signal transduction. Curr Opin Microbiol 2000, 3(2):165-170.
8. Stock AM, Robinson VL, Goudreau PN: Two-component signal transduction. Annu Rev Biochem 2000, 69:183-215.
9. West AH, Stock AM: Histidine kinases and response regulator proteins in two-component signaling systems. Trends Biochem Sci 2001, 26(6):369-376.
10. Stock AM, West AH: Response Regulator Proteins and their interactions with histidine protein kinases. Histidine Kinases in Signal Transduction 2003, Academic Press:237-271.
11. Tsuzuki M, Ishige K, Mizuno T: Phosphotransfer circuitry of the putative multi-signal transducer, ArcB, of Escherichia coli: in vitro studies with mutants. Mol Microbiol 1995, 18(5):953-962.
12. Georgellis D, Lynch AS, Lin EC: In vitro phosphorylation study of the arc two-component signal transduction system of Escherichia coli. J Bacteriol 1997, 179(17):5429-5435.
13. Tomenius H, Pernestig AK, Mendez-Catala CF, Georgellis D, Normark S, Melefors O: Genetic and functional characterization of the Escherichia coli BarA-UvrY two-component system: point mutations in the HAMP linker of the BarA sensor give a dominant-negative phenotype. J Bacteriol 2005, 187(21):7317-7324.
14. Uhl MA, Miller JF: Integration of multiple domains in a two-component sensor protein: the Bordetella pertussis BvgAS phosphorelay. Embo J 1996, 15(5):1028-1036.
15. Jourlin C, Ansaldi M, Mejean V: Transphosphorylation of the TorR response regulator requires the three phosphorylation sites of the TorS unorthodox sensor in Escherichia coli. J Mol Biol 1997, 267(4):770-777.
16. Sahu SN, Acharya S, Tuminaro H, Patel I, Dudley K, LeClerc JE, Cebula TA, Mukhopadhyay S: The bacterial adaptive response gene, barA, encodes a novel conserved histidine kinase regulatory switch for adaptation and modulation of metabolism in Escherichia coli. Mol Cell Biochem 2003, 253(1-2):167-177.
17. Laub MT, Goulian M: Specificity in two-component signal transduction pathways. Annu Rev Genet 2007, 41:121-145.
18. Tischler AD, Lee SH, Camilli A: The Vibrio cholerae vieSAB locus encodes a pathway contributing to cholera toxin production. J Bacteriol 2002, 184(15):4104-4113.
19. Kulasekara HD, Ventre I, Kulasekara BR, Lazdunski A, Filloux A, Lory S: A novel two-component system controls the expression of Pseudomonas aeruginosa fimbrial cup genes. Mol Microbiol 2005, 55(2):368-380.
20. Ventre I, Goodman AL, Vallet-Gely I, Vasseur P, Soscia C, Molin S, Bleves S, Lazdunski A, Lory S, Filloux A: Multiple sensors control reciprocal expression of Pseudomonas aeruginosa regulatory RNA and virulence genes. Proc Natl Acad Sci U S A 2006, 103(1):171-176.
21. Armitage JP: Bacterial tactic responses. Adv Microb Physiol 1999, 41:229-289.
22. Baker MD, Wolanin PM, Stock JB: Signal transduction in bacterial chemotaxis. Bioessays 2006, 28(1):9-22.
23. Mascher T, Helmann JD, Unden G: Stimulus perception in bacterial signal-transducing histidine kinases. Microbiol Mol Biol Rev 2006, 70(4):910-938.
24. Ulrich LE, Koonin EV, Zhulin IB: One-component systems dominate signal transduction in prokaryotes. Trends Microbiol 2005, 13(2):52-56.
25. Galperin MY: Bacterial signal transduction network in a genomic perspective. Environ Microbiol 2004, 6(6):552-567.
26. Galperin MY, Nikolskaya AN, Koonin EV: Novel domains of the prokaryotic two-component signal transduction systems. FEMS Microbiol Lett 2001, 203(1):11-21.
27. Unden G, Guest JR: Isolation and characterization of the Fnr protein, the transcriptional regulator of anaerobic electron transport in Escherichia coli. Eur J Biochem 1985, 146(1):193-199.
28. Trageser M, Unden G: Role of cysteine residues and of metal ions in the regulatory functioning of FNR, the transcriptional regulator of anaerobic respiration in Escherichia coli. Mol Microbiol 1989, 3(5):593-599.
29. Unden G, Becker S, Bongaerts J, Holighaus G, Schirawski J, Six S: O2-sensing and O2-dependent gene regulation in facultatively anaerobic bacteria. Arch Microbiol 1995, 164(2):81-90.
30. Hoffman LR, D'Argenio DA, MacCoss MJ, Zhang Z, Jones RA, Miller SI:
Aminoglycoside antibiotics induce bacterial biofilm formation. Nature 2005, 436(7054):1171-1175.
31. Helmann JD: The extracytoplasmic function (ECF) sigma factors. Adv Microb Physiol 2002, 46:47-110.
32. Brooks BE, Buchanan SK: Signaling mechanisms for activation of extracytoplasmic function (ECF) sigma factors. Biochim Biophys Acta 2008, 1778(9):1930-1945.
33. Burgess RR, Travers AA: Escherichia coli RNA polymerase: purification, subunit structure, and factor requirements. Fed Proc 1970, 29(3):1164-1169.
34. Burgess RR, Travers AA, Dunn JJ, Bautz EK: Factor stimulating transcription by RNA polymerase. Nature 1969, 221(5175):43-46.
35. Helmann JD: Anti-sigma factors. Current Opinion in Microbiology 1999, 2:135-141
36. Chamberlin MJ: The selectivity of transcription. Annu Rev Biochem 1974, 43(0):721-775.
37. Reznikoff WS, Siegele DA, Cowing DW, Gross CA: The regulation of transcription initiation in bacteria. Annu Rev Genet 1985, 19:355-387.
38. Wosten MM: Eubacterial sigma-factors. FEMS Microbiol Rev 1998, 22(3):127-150.
39. Ishihama A: Functional modulation of Escherichia coli RNA polymerase.
Annu Rev Microbiol 2000, 54:499-518.
40. Kazmierczak MJ, Wiedmann M, Boor KJ: Alternative sigma factors and their roles in bacterial virulence. Microbiol Mol Biol Rev 2005, 69(4):527-543.
41. Botsford JL, Harman JG: Cyclic AMP in prokaryotes. Microbiol Rev 1992, 56(1):100-122.
42. Bruckner R, Titgemeyer F: Carbon catabolite repression in bacteria: choice of the carbon source and autoregulatory limitation of sugar utilization.
FEMS Microbiol Lett 2002, 209(2):141-148.
43. Kolb A, Busby S, Buc H, Garges S, Adhya S: Transcriptional regulation by cAMP and its receptor protein. Annu Rev Biochem 1993, 62:749-795.
44. Korner H, Sofia HJ, Zumft WG: Phylogeny of the bacterial superfamily of Crp-Fnr transcription regulators: exploiting the metabolic spectrum by controlling alternative gene programs. FEMS Microbiol Rev 2003, 27(5):559-592.
45. Xu M, Su Z: Computational prediction of cAMP receptor protein (CRP) binding sites in cyanobacterial genomes. BMC Genomics 2009, 10:23.
46. Laub MT, Chen SL, Shapiro L, McAdams HH: Genes directly controlled by CtrA, a master regulator of the Caulobacter cell cycle. Proc Natl Acad Sci U S A 2002, 99(7):4632-4637.
47. Romeo T: Global regulation by the small RNA-binding protein CsrA and the non-coding RNA molecule CsrB. Mol Microbiol 1998, 29(6):1321-1330.
48. Babitzke P, Romeo T: CsrB sRNA family: sequestration of RNA-binding regulatory proteins. Curr Opin Microbiol 2007, 10(2):156-163.
49. Lawhon SD, Frye JG, Suyemoto M, Porwollik S, McClelland M, Altier C:
Global regulation by CsrA in Salmonella typhimurium. Mol Microbiol 2003, 48(6):1633-1645.
50. Andrade JM, Arraiano CM: PNPase is a key player in the regulation of small RNAs that control the expression of outer membrane proteins. Rna 2008, 14(3):543-551.
51. Clements MO, Eriksson S, Thompson A, Lucchini S, Hinton JC, Normark S, Rhen M: Polynucleotide phosphorylase is a global regulator of virulence and persistency in Salmonella enterica. Proc Natl Acad Sci U S A 2002, 99(13):8784-8789.
52. Viegas SC, Pfeiffer V, Sittka A, Silva IJ, Vogel J, Arraiano CM:
Characterization of the role of ribonucleases in Salmonella small RNA decay. Nucleic Acids Res 2007, 35(22):7651-7664.
53. Alon U: Network motifs: theory and experimental approaches. Nat Rev Genet 2007, 8(6):450-461.
54. Storz G: An expanding universe of noncoding RNAs. Science 2002, 296(5571):1260-1263.
55. Storz G, Altuvia S, Wassarman KM: An abundance of RNA regulators. Annu Rev Biochem 2005, 74:199-217.
56. Gottesman S: Small RNAs shed some light. Cell 2004, 118(1):1-2.
57. Brantl S: Bacterial chromosome-encoded small regulatory RNAs. Future Microbiol 2009, 4:85-103.
58. Brantl S: Antisense-RNA regulation and RNA interference. Biochim Biophys Acta 2002, 1575(1-3):15-25.
59. Brantl S: Regulatory mechanisms employed by cis-encoded antisense RNAs. Curr Opin Microbiol 2007, 10(2):102-109.
60. Opdyke JA, Kang JG, Storz G: GadY, a small-RNA regulator of acid response genes in Escherichia coli. J Bacteriol 2004, 186(20):6698-6705.
61. Lapouge K, Schubert M, Allain FH, Haas D: Gac/Rsm signal transduction pathway of gamma-proteobacteria: from RNA recognition to regulation of social behaviour. Mol Microbiol 2008, 67(2):241-253.
62. Liu MY, Romeo T: The global regulator CsrA of Escherichia coli is a specific mRNA-binding protein. J Bacteriol 1997, 179(14):4639-4642.
63. Suzuki K, Wang X, Weilbacher T, Pernestig AK, Melefors O, Georgellis D, Babitzke P, Romeo T: Regulatory circuitry of the CsrA/CsrB and BarA-UvrY systems of Escherichia coli. J Bacteriol 2002, 184(18):5130-5140.
64. Papenfort K, Pfeiffer V, Mika F, Lucchini S, Hinton JC, Vogel J: SigmaE-dependent small RNAs of Salmonella respond to membrane stress by accelerating global omp mRNA decay. Mol Microbiol 2006, 62(6):1674-1688.
65. Valverde C, Haas D: Small RNAs controlled by two-component systems.
Adv Exp Med Biol 2008, 631:54-79.
66. Romling U, Amikam D: Cyclic di-GMP as a second messenger. Curr Opin Microbiol 2006, 9(2):218-228.
67. Romling U, Gomelsky M, Galperin MY: C-di-GMP: the dawning of a novel bacterial signalling system. Mol Microbiol 2005, 57(3):629-639.
68. Jenal U: Cyclic di-guanosine-monophosphate comes of age: a novel secondary messenger involved in modulating cell surface structures in bacteria? Curr Opin Microbiol 2004, 7(2):185-191.
69. Jenal U, Malone J: Mechanisms of cyclic-di-GMP signaling in bacteria.
Annu Rev Genet 2006, 40:385-407.
70. Ausmees N, Mayer R, Weinhouse H, Volman G, Amikam D, Benziman M, Lindberg M: Genetic data indicate that proteins containing the GGDEF domain possess diguanylate cyclase activity. FEMS Microbiol Lett 2001, 204(1):163-167.
71. Tal R, Wong HC, Calhoon R, Gelfand D, Fear AL, Volman G, Mayer R, Ross P, Amikam D, Weinhouse H 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 1998, 180(17):4416-4425.
72. 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 2005, 280(35):30829-30837.
73. Paul R, Weiser S, Amiot NC, Chan C, Schirmer T, Giese B, Jenal U: Cell cycle-dependent dynamic localization of a bacterial response regulator with a novel di-guanylate cyclase output domain. Genes Dev 2004, 18(6):715-727.
74. Ryan RP, Fouhy Y, Lucey JF, Crossman LC, Spiro S, He YW, Zhang LH, Heeb S, Camara M, Williams 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 U S A 2006, 103(17):6712-6717.
75. Ryjenkov DA, Tarutina M, Moskvin OV, Gomelsky M: Cyclic diguanylate is a ubiquitous signaling molecule in bacteria: insights into biochemistry of the GGDEF protein domain. J Bacteriol 2005, 187(5):1792-1798.
76. Simm R, Morr M, Kader A, Nimtz M, Romling U: GGDEF and EAL domains inversely regulate cyclic di-GMP levels and transition from sessility to motility. Mol Microbiol 2004, 53(4):1123-1134.
77. Tamayo R, Tischler AD, Camilli A: The EAL domain protein VieA is a cyclic diguanylate phosphodiesterase. J Biol Chem 2005, 280(39):33324-33330.
78. Romling U: Characterization of the rdar morphotype, a multicellular behaviour in Enterobacteriaceae. Cell Mol Life Sci 2005, 62(11):1234-1246.
79. Costerton JW, Lewandowski Z, Caldwell DE, Korber DR, Lappin-Scott HM:
Microbial biofilms. Annu Rev Microbiol 1995, 49:711-745.
80. Tamayo R, Pratt JT, Camilli A: Roles of cyclic diguanylate in the regulation of bacterial pathogenesis. Annu Rev Microbiol 2007, 61:131-148.
81. Cotter PA, Stibitz S: c-di-GMP-mediated regulation of virulence and biofilm formation. Curr Opin Microbiol 2007, 10(1):17-23.
82. Tischler AD, Camilli A: Cyclic diguanylate regulates Vibrio cholerae virulence gene expression. Infect Immun 2005, 73(9):5873-5882.
83. Kulasakara H, Lee V, Brencic A, Liberati N, Urbach J, Miyata S, Lee DG, Neely AN, Hyodo M, Hayakawa Y et al: Analysis of Pseudomonas aeruginosa diguanylate cyclases and phosphodiesterases reveals a role for bis-(3'-5')-cyclic-GMP in virulence. Proc Natl Acad Sci U S A 2006, 103(8):2839-2844.
84. Hisert KB, MacCoss M, Shiloh MU, Darwin KH, Singh S, Jones RA, Ehrt S, Zhang Z, Gaffney BL, Gandotra S et al: A glutamate-alanine-leucine (EAL) domain protein of Salmonella controls bacterial survival in mice,
antioxidant defence and killing of macrophages: role of cyclic diGMP. Mol Microbiol 2005, 56(5):1234-1245.
85. Rogers EA, Terekhova D, Zhang HM, Hovis KM, Schwartz I, Marconi RT:
Rrp1, a cyclic-di-GMP-producing response regulator, is an important regulator of Borrelia burgdorferi core cellular functions. Mol Microbiol 2009.
86. Ryjenkov DA, Simm R, Romling U, Gomelsky M: The PilZ domain is a receptor for the second messenger c-di-GMP: the PilZ domain protein YcgR controls motility in enterobacteria. J Biol Chem 2006, 281(41):30310-30314.
87. Amikam D, Galperin MY: PilZ domain is part of the bacterial c-di-GMP binding protein. Bioinformatics 2006, 22(1):3-6.
88. Hickman JW, Harwood CS: Identification of FleQ from Pseudomonas aeruginosa as a c-di-GMP-responsive transcription factor. Mol Microbiol 2008, 69(2):376-389.
89. Lee VT, Matewish JM, Kessler JL, Hyodo M, Hayakawa Y, Lory S: A cyclic-di-GMP receptor required for bacterial exopolysaccharide production. Mol Microbiol 2007, 65(6):1474-1484.
90. Sudarsan N, Lee ER, Weinberg Z, Moy RH, Kim JN, Link KH, Breaker RR:
Riboswitches in eubacteria sense the second messenger cyclic di-GMP.
Science 2008, 321(5887):411-413.
91. Garcia B, Latasa C, Solano C, Garcia-del Portillo F, Gamazo C, Lasa I: Role of the GGDEF protein family in Salmonella cellulose biosynthesis and biofilm formation. Mol Microbiol 2004, 54(1):264-277.
92. Schmidt AJ, Ryjenkov DA, Gomelsky M: The ubiquitous protein domain EAL is a cyclic diguanylate-specific phosphodiesterase: enzymatically active and inactive EAL domains. J Bacteriol 2005, 187(14):4774-4781.
93. Ferreira RB, Antunes LC, Greenberg EP, McCarter LL: Vibrio parahaemolyticus ScrC modulates cyclic dimeric GMP regulation of gene expression relevant to growth on surfaces. J Bacteriol 2008, 190(3):851-860.
94. Tarutina M, Ryjenkov DA, Gomelsky M: An unorthodox bacteriophytochrome from Rhodobacter sphaeroides involved in turnover of the second messenger c-di-GMP. J Biol Chem 2006, 281(46):34751-34758.
95. Suzuki K, Babitzke P, Kushner SR, 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 2006, 20(18):2605-2617.
96. Newell PD, Monds RD, O'Toole GA: LapD is a bis-(3',5')-cyclic dimeric GMP-binding protein that regulates surface attachment by Pseudomonas fluorescens Pf0-1. Proc Natl Acad Sci U S A 2009, 106(9):3461-3466.
97. Duerig A, Abel S, Folcher M, Nicollier M, Schwede T, Amiot N, Giese B, Jenal U: Second messenger-mediated spatiotemporal control of protein degradation regulates bacterial cell cycle progression. Genes Dev 2009, 23(1):93-104.
98. Beyhan S, Odell LS, Yildiz FH: Identification and characterization of cyclic diguanylate signaling systems controlling rugosity in Vibrio cholerae. J Bacteriol 2008, 190(22):7392-7405.
99. Holland LM, O'Donnell ST, Ryjenkov DA, Gomelsky L, Slater SR, Fey PD, Gomelsky M, O'Gara JP: A staphylococcal GGDEF domain protein regulates biofilm formation independently of cyclic dimeric GMP. J Bacteriol 2008, 190(15):5178-5189.
100. Tschowri N, Busse S, Hengge R: The BLUF-EAL protein YcgF acts as a direct anti-repressor in a blue-light response of Escherichia coli. Genes Dev 2009, 23(4):522-534.
101. Jonas K, Melefors O, Romling U: Concerted and Specific Regulation of c-di-GMP metabolism. Future Microbiol 2009.
102. Potrykus K, Cashel M: (p)ppGpp: still magical? Annu Rev Microbiol 2008, 62:35-51.
103. Magnusson LU, Farewell A, Nystrom T: ppGpp: a global regulator in Escherichia coli. Trends Microbiol 2005, 13(5):236-242.
104. Srivatsan A, Wang JD: Control of bacterial transcription, translation and replication by (p)ppGpp. Curr Opin Microbiol 2008, 11(2):100-105.
105. Witte G, Hartung S, Buttner K, Hopfner KP: Structural biochemistry of a bacterial checkpoint protein reveals diadenylate cyclase activity regulated by DNA recombination intermediates. Mol Cell 2008, 30(2):167-178.
106. Romling U: Great times for small molecules: c-di-AMP, a second messenger candidate in Bacteria and Archaea. Sci Signal 2008, 1(33):pe39.
107. Wolfe AJ, Chang DE, Walker JD, Seitz-Partridge JE, Vidaurri MD, Lange CF, Pruss BM, Henk MC, Larkin JC, Conway T: Evidence that acetyl phosphate functions as a global signal during biofilm development. Mol Microbiol 2003, 48(4):977-988.
108. Wolfe AJ: The acetate switch. Microbiol Mol Biol Rev 2005, 69(1):12-50.
109. Ault-Riche D, Fraley CD, Tzeng CM, Kornberg A: Novel assay reveals multiple pathways regulating stress-induced accumulations of inorganic polyphosphate in Escherichia coli. J Bacteriol 1998, 180(7):1841-1847.
110. Lakaye B, Wirtzfeld B, Wins P, Grisar T, Bettendorff L: Thiamine triphosphate, a new signal required for optimal growth of Escherichia coli during amino acid starvation. J Biol Chem 2004, 279(17):17142-17147.
111. Miller MB, Bassler BL: Quorum sensing in bacteria. Annu Rev Microbiol 2001, 55:165-199.
112. Bassler BL: Small talk. Cell-to-cell communication in bacteria. Cell 2002, 109(4):421-424.
113. Waters CM, Bassler BL: Quorum sensing: cell-to-cell communication in bacteria. Annu Rev Cell Dev Biol 2005, 21:319-346.
114. Lyon GJ, Novick RP: Peptide signaling in Staphylococcus aureus and other Gram-positive bacteria. Peptides 2004, 25(9):1389-1403.
115. Lowery CA, Dickerson TJ, Janda KD: Interspecies and interkingdom communication mediated by bacterial quorum sensing. Chem Soc Rev 2008, 37(7):1337-1346.
116. Xavier KB, Bassler BL: LuxS quorum sensing: more than just a numbers game. Curr Opin Microbiol 2003, 6(2):191-197.
117. Camilli A, Bassler BL: Bacterial small-molecule signaling pathways. Science 2006, 311(5764):1113-1116.
118. Waters CM, Lu W, Rabinowitz JD, Bassler BL: Quorum sensing controls biofilm formation in Vibrio cholerae through modulation of cyclic di-GMP levels and repression of vpsT. J Bacteriol 2008, 190(7):2527-2536.
119. Dow JM, Fouhy Y, Lucey JF, Ryan RP: The HD-GYP domain, cyclic di-GMP signaling, and bacterial virulence to plants. Mol Plant Microbe Interact 2006, 19(12):1378-1384.
120. Fouhy Y, Lucey JF, Ryan RP, Dow JM: Cell-cell signaling, cyclic di-GMP turnover and regulation of virulence in Xanthomonas campestris. Res Microbiol 2006, 157(10):899-904.
121. Mercante J, Suzuki K, Cheng X, Babitzke P, Romeo T: Comprehensive alanine-scanning mutagenesis of Escherichia coli CsrA defines two subdomains of critical functional importance. J Biol Chem 2006, 281(42):31832-31842.
122. Schubert M, Lapouge K, Duss O, Oberstrass FC, Jelesarov I, Haas D, Allain FH: Molecular basis of messenger RNA recognition by the specific bacterial repressing clamp RsmA/CsrA. Nat Struct Mol Biol 2007, 14(9):807-813.
123. Gutierrez P, Li Y, Osborne MJ, Pomerantseva E, Liu Q, Gehring K: Solution structure of the carbon storage regulator protein CsrA from Escherichia coli. J Bacteriol 2005, 187(10):3496-3501.
124. Rife C, Schwarzenbacher R, McMullan D, Abdubek P, Ambing E, Axelrod H, Biorac T, Canaves JM, Chiu HJ, Deacon AM et al: Crystal structure of the