Regulation by cyclic di-GMP in Myxococcus xanthus

The nucleotide-based second messenger bis-(3’-5’)-cyclic dimeric GMP (c-di-GMP) is involved in regulating a plethora of processes in bacteria that are typically associated with lifestyle changes. Myxococcus xanthus undergoes major lifestyle changes in response to nutrient availability with the forma...

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1. Verfasser: Skotnicka, Dorota
Beteiligte: Søgaard-Andersen, Lotte (Prof. Dr.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Englisch
Veröffentlicht: Philipps-Universität Marburg 2016
Biologie
Ausgabe:http://dx.doi.org/10.17192/z2016.0101
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publishDate 2016
era_facet 2016
topic Myxococcus xanthus
Exopolysaccharide
cyclic di-GMP
diguanylate cyclase
exopolysaccharide
Biowissenschaften, Biologie
cyclisches-di-GMP
Myxococcus xanthus
Diguanylatzyklase
spellingShingle Myxococcus xanthus
Exopolysaccharide
cyclic di-GMP
diguanylate cyclase
exopolysaccharide
Biowissenschaften, Biologie
cyclisches-di-GMP
Myxococcus xanthus
Diguanylatzyklase
Skotnicka, Dorota
Regulation by cyclic di-GMP in Myxococcus xanthus
Der nukleotid-basierte, sekundäre Botenstoff bis-(3‘-5‘)-cyclic GMP (c-di-GMP) ist an einer Vielzahl von regulatorischen Prozessen im Zusammenhang mit Veränderungen des Lebenszyklusses in Bakterien beteiligt. Myxococcus xanthus reagiert entsprechend der Nährstoffverfügbarkeit in seiner Umgebung. Bei ausreichenden Nährstoffen bildet M. xanthus sich ausbreitende Kolonien. Unter nahrungslimitierenden Bedingungen hingegen werden mit Sporen gefüllte Fruchtkörper geformt. In dieser Arbeit wurde die Funktion von c-di-GMP in M. xanthus untersucht. M. xanthus kann c-di-GMP produzieren. Die Manipulation der zellulären c-di-GMP Konzentration durch Expression einer heterologen, aktiven Diguanylatzyklase oder Phosphodiesterase in lebenden Zellen führte zu einem Defekt der „type-IV-pili“ (T4P) abhängigen Beweglichkeit. Die Gleitbewegung von M. xanthus hingegen blieb dadurch unberührt. Eine erhöhte Konzentration von c-di-GMP reduzierte die Transkription des pilA Genes, welches für das wichtigste Pilin des T4P codiert, reduzierte das Vorkommen von T4P generell und veränderte die Zellagglutination. Ein niedriges Niveau von c-di-GMP führte lediglich zu veränderter Zellagglutination. Die systematische Inaktivierung von 24 Genen in M. xanthus, welche für Proteine mit GGDEF, EAL oder HD-GYP Domänen kodieren, die im Zusammenhang mit der Synthetisierung, dem Abbau oder dem Binden von c-di-GMP stehen, identifizierte drei Gene, die wichtig für die T4P abhängige Bewegung sind. Die dazugehörigen Proteine DmxA, TmoK und SgmT enthalten alle eine GGDEF Domäne. DmxA besitzt Diguanylatzyklaseaktivität, TmoK und SgmT (beide Hybrid Histidinkinasen) zeigen keine Diguanylatzyklaseaktivität in vitro. Die Konzentration von c-di-GMP steigt während nahrungslimitierenden Bedingungen signifikant an. Artifiziell herbeigeführtes niedriges c-di-GMP Niveau beeinflusst das Entwicklungsprogramm, hohes jedoch nicht. Zudem konnten wir aus den 24 Genen, die für Proteine mit GGDEF, EAL und HD-GYP Domänen kodieren, zwei Gene identifizieren, welche spezifisch im Entwicklungsprogramm von M. xanthus involviert sind: pmxA und dmxB. pmxA kodiert für eine enzymatisch aktive Phosphodiesterase mit einer HD-GYP-Domäne. dmxB kodiert für eine im Entwicklungsprogramm induzierte, enzymatisch aktive Diguanylatzyklase. DmxB ist essentiell um ein erhöhtes c-di-GMP Niveau in den Zellen aufrechtzuerhalten und reguliert außerdem Exopolysaccharide während des Nährstoffmangels. Unsere Resultate zeigen, dass c-di-GMP ein wichtiges Signalmolekül im Entwicklungsprogramm von M. xanthus ist und weist auf ein Model hin, in dem ein minimaler Schwellenwert an c-di-GMP Konzentration erreicht sein muss, um ein erfolgreiches Fortschreiten des Entwicklungsprogrammes zu gewährleisten. Zusätzlich konnten wir c-di-GMP spezifische Effektormoleküle mit Hilfe von Massenspektrometrie identifizieren und teilweise charakterisieren. Für einige dieser Kandidaten konnte bestätigt werden, dass sie in vitro c-di-GMP binden und die Deletionsmutanten der korrespodierenden Gene wurden hinsichtlich ihrer Fähigkeit des T4P abhängigen Beweglichkeit und ihres Entwicklungsprogrammes charakterisiert.
author Skotnicka, Dorota
ref_str_mv references
institution Biologie
description The nucleotide-based second messenger bis-(3’-5’)-cyclic dimeric GMP (c-di-GMP) is involved in regulating a plethora of processes in bacteria that are typically associated with lifestyle changes. Myxococcus xanthus undergoes major lifestyle changes in response to nutrient availability with the formation of spreading colonies in the presence of nutrients and spore-filled fruiting bodies in the absence of nutrients. Here, we investigated the function of c-di-GMP in M. xanthus. We show that this bacterium synthesizes c-di-GMP. Manipulation of the cellular c-di-GMP level by expression of either an active, heterologous diguanylate cyclase or an active, heterologous phosphodiesterase in vegetative cells caused defects in type IV pili (T4P)-dependent motility whereas gliding motility was unaffected. An increased level of c-di-GMP caused reduced transcription of the pilA gene that encodes the major pilin of T4P, reduced assembly of T4P and altered cell agglutination whereas a decreased level of c-di-GMP caused altered cell agglutination. The systematic inactivation of the 24 genes in M. xanthus encoding proteins containing GGDEF, EAL or HD-GYP domains, which are associated with c-di-GMP synthesis, degradation or binding, identified three genes encoding proteins important for T4P-dependent motility. These three proteins named DmxA, TmoK and SgmT all contain a GGDEF domain. Purified DmxA had diguanylate cyclase activity whereas the TmoK and SgmT (both hybrid histidine protein kinases) did not have diguanylate cyclase activity. During starvation, the c-di-GMP level in M. xanthus increases significantly. Manipulation of this level revealed that a low c-di-GMP level negatively affects the developmental program while an increased level does not interfere with development. Moreover, among the 24 genes encoding proteins containing GGDEF, EAL or HD-GYP domains, we identified two which are specifically involved in development: pmxA and dmxB. pmxA codes for an enzymatically active phosphodiesterase with an HD-GYP domain. dmxB codes for a developmentally induced, enzymatically active diguanylate cyclase. DmxB is essential for the increased c-di-GMP level and regulates exopolysaccharide accumulation during starvation. Our results show that c-di-GMP acts as an important signaling molecule during M. xanthus development, and suggest a model in which a minimal threshold level of c-di-GMP is essential for the successful progression and completion of the developmental program. Additionally, candidates for c-di-GMP effectors in M. xanthus were identified using a capture compound mass spectrometry approach. Some of the candidates were confirmed to bind c-di-GMP in vitro and deletion mutants for genes encoding those proteins were characterized in terms of T4P-dependent motility and development.
physical 134 pages.
format Dissertation
oai_set_str_mv doc-type:doctoralThesis
open_access
ddc:570
xMetaDissPlus
title_alt Regulation durch cyclisches-di-GMP in Myxococcus xanthus
author2 Søgaard-Andersen, Lotte (Prof. Dr.)
author2_role ths
doi_str_mv http://dx.doi.org/10.17192/z2016.0101
edition http://dx.doi.org/10.17192/z2016.0101
building Fachbereich Biologie
first_indexed 2016-04-14T00:00:00Z
last_indexed 2016-04-14T23:59:59Z
license_str https://creativecommons.org/licenses/by/4.0
dewey-raw 570
dewey-search 570
genre Life sciences
genre_facet Life sciences
topic_facet Biowissenschaften, Biologie
url http://archiv.ub.uni-marburg.de/diss/z2016/0101/pdf/dDS.pdf
language English
title Regulation by cyclic di-GMP in Myxococcus xanthus
title_short Regulation by cyclic di-GMP in Myxococcus xanthus
title_full Regulation by cyclic di-GMP in Myxococcus xanthus
title_fullStr Regulation by cyclic di-GMP in Myxococcus xanthus
title_full_unstemmed Regulation by cyclic di-GMP in Myxococcus xanthus
title_sort Regulation by cyclic di-GMP in Myxococcus xanthus
publisher Philipps-Universität Marburg
contents Der nukleotid-basierte, sekundäre Botenstoff bis-(3‘-5‘)-cyclic GMP (c-di-GMP) ist an einer Vielzahl von regulatorischen Prozessen im Zusammenhang mit Veränderungen des Lebenszyklusses in Bakterien beteiligt. Myxococcus xanthus reagiert entsprechend der Nährstoffverfügbarkeit in seiner Umgebung. Bei ausreichenden Nährstoffen bildet M. xanthus sich ausbreitende Kolonien. Unter nahrungslimitierenden Bedingungen hingegen werden mit Sporen gefüllte Fruchtkörper geformt. In dieser Arbeit wurde die Funktion von c-di-GMP in M. xanthus untersucht. M. xanthus kann c-di-GMP produzieren. Die Manipulation der zellulären c-di-GMP Konzentration durch Expression einer heterologen, aktiven Diguanylatzyklase oder Phosphodiesterase in lebenden Zellen führte zu einem Defekt der „type-IV-pili“ (T4P) abhängigen Beweglichkeit. Die Gleitbewegung von M. xanthus hingegen blieb dadurch unberührt. Eine erhöhte Konzentration von c-di-GMP reduzierte die Transkription des pilA Genes, welches für das wichtigste Pilin des T4P codiert, reduzierte das Vorkommen von T4P generell und veränderte die Zellagglutination. Ein niedriges Niveau von c-di-GMP führte lediglich zu veränderter Zellagglutination. Die systematische Inaktivierung von 24 Genen in M. xanthus, welche für Proteine mit GGDEF, EAL oder HD-GYP Domänen kodieren, die im Zusammenhang mit der Synthetisierung, dem Abbau oder dem Binden von c-di-GMP stehen, identifizierte drei Gene, die wichtig für die T4P abhängige Bewegung sind. Die dazugehörigen Proteine DmxA, TmoK und SgmT enthalten alle eine GGDEF Domäne. DmxA besitzt Diguanylatzyklaseaktivität, TmoK und SgmT (beide Hybrid Histidinkinasen) zeigen keine Diguanylatzyklaseaktivität in vitro. Die Konzentration von c-di-GMP steigt während nahrungslimitierenden Bedingungen signifikant an. Artifiziell herbeigeführtes niedriges c-di-GMP Niveau beeinflusst das Entwicklungsprogramm, hohes jedoch nicht. Zudem konnten wir aus den 24 Genen, die für Proteine mit GGDEF, EAL und HD-GYP Domänen kodieren, zwei Gene identifizieren, welche spezifisch im Entwicklungsprogramm von M. xanthus involviert sind: pmxA und dmxB. pmxA kodiert für eine enzymatisch aktive Phosphodiesterase mit einer HD-GYP-Domäne. dmxB kodiert für eine im Entwicklungsprogramm induzierte, enzymatisch aktive Diguanylatzyklase. DmxB ist essentiell um ein erhöhtes c-di-GMP Niveau in den Zellen aufrechtzuerhalten und reguliert außerdem Exopolysaccharide während des Nährstoffmangels. Unsere Resultate zeigen, dass c-di-GMP ein wichtiges Signalmolekül im Entwicklungsprogramm von M. xanthus ist und weist auf ein Model hin, in dem ein minimaler Schwellenwert an c-di-GMP Konzentration erreicht sein muss, um ein erfolgreiches Fortschreiten des Entwicklungsprogrammes zu gewährleisten. Zusätzlich konnten wir c-di-GMP spezifische Effektormoleküle mit Hilfe von Massenspektrometrie identifizieren und teilweise charakterisieren. Für einige dieser Kandidaten konnte bestätigt werden, dass sie in vitro c-di-GMP binden und die Deletionsmutanten der korrespodierenden Gene wurden hinsichtlich ihrer Fähigkeit des T4P abhängigen Beweglichkeit und ihres Entwicklungsprogrammes charakterisiert.
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Choi, (2011) Structural characterization reveals that a PilZ domain protein undergoes substantial conformational change upon binding to cyclic dimeric guanosine monophosphate. Protein Sci 20: 270- 277. 2011 Structural characterization reveals that a PilZ domain protein undergoes substantial conformational change upon binding to cyclic dimeric guanosine monophosphate Bordeleau, E., L.C. Fortier, F. Malouin & V. Burrus, (2011) c-di-GMP turn-over in Clostridium difficile is controlled by a plethora of diguanylate cyclases and phosphodiesterases. PLoS Genetics 7: e1002039. 2011 c-di-GMP turn-over in Clostridium difficile is controlled by a plethora of diguanylate cyclases and phosphodiesterases Habazettl, J., M.G. Allan, U. Jenal & S. Grzesiek, (2011) Solution Structure of the PilZ Domain Protein PA4608 Complex with Cyclic di-GMP Identifies Charge Clustering as Molecular Readout. J Biol Chem 286: 14304-14314. 2011 Solution Structure of the PilZ Domain Protein PA4608 Complex with Cyclic di-GMP Identifies Charge Clustering as Molecular Readout Gomelsky, M., (2011) cAMP, c-di-GMP, c-di-AMP and now cGMP: bacteria use them all! Mol Microbiol 79: 562-565. 2011) cAMP, c-di-GMP, c-di-AMP and now cGMP: bacteria use them all Sun, M., M. Wartel, E. Cascales, J.W. Shaevitz & T. Mignot, (2011) Motor-driven intracellular transport powers bacterial gliding motility. Proc Natl Acad Sci USA 108: 7559-7564. 2011 Motor-driven intracellular transport powers bacterial gliding motility Sultan, S.Z., J. E. Pitzer, T. Boquoi, G. Hobbs, M.R. Miller & M. A. Motaleb, (2011) Analysis of the HD-GYP domain cyclic dimeric GMP phosphodiesterase reveals a role in motility and the enzootic life cycle of Borrelia burgdorferi. Infect. Immun. 79: 3273-3283. 2011 Analysis of the HD-GYP domain cyclic dimeric GMP phosphodiesterase reveals a role in motility and the enzootic life cycle of Borrelia burgdorferi Giglio, K.M., N. Caberoy, G. Suen, D. Kaiser & A.G. Garza, (2011) A cascade of coregulating enhancer binding proteins initiates and propagates a multicellular developmental program. Proc Natl Acad Sci USA 108: E431–E439. 2011 A cascade of coregulating enhancer binding proteins initiates and propagates a multicellular developmental program Harris, B.Z., D. Kaiser & M. Singer, (1998) The guanosine nucleotide (p)ppGpp initiates development and A-factor production in Myxococcus xanthus. Genes & development 12: 1022-1035. 1998 The guanosine nucleotide (p)ppGpp initiates development and A-factor production in Myxococcus xanthus Luciano, J., R. Agrebi, A.V. Le Gall, M. Wartel, F. Fiegna, A. Ducret, C. Brochier- Armanet & T. Mignot, (2011) Emergence and modular evolution of a novel motility machinery in bacteria. PLoS genetics 7: e1002268. 2011 Emergence and modular evolution of a novel motility machinery in bacteria Roelofs, K.G., J.X. Wang, H.O. Sintim & V.T. Lee, (2011) Differential radial capillary action of ligand assay for high-throughput detection of protein-metabolite interactions. Proc Natl Acad Sci USA 108: 15528-15533. 2011 Differential radial capillary action of ligand assay for high-throughput detection of protein-metabolite interactions Srivastava, D., R.C. Harris & C.M. Waters, (2011) Integration of cyclic di-GMP and quorum sensing in the control of vpsT and aphA in Vibrio cholerae. J Bacteriol 193: 6331-6341. 2011 Integration of cyclic di-GMP and quorum sensing in the control of vpsT and aphA in Vibrio cholerae Bretl, D.J., C. Demetriadou & T.C. Zahrt, (2011) Adaptation to Environmental Stimuli within the Host: Two-Component Signal Transduction Systems of Mycobacterium tuberculosis. Microbiol Mol Biol R 75: 566-582. 2011 Adaptation to Environmental Stimuli within the Host: Two-Component Signal Transduction Systems of Mycobacterium tuberculosis Shikuma, N.J., J.C. Fong & F.H. Yildiz, (2012) Cellular levels and binding of c-di-GMP control subcellular localization and activity of the Vibrio cholerae transcriptional regulator VpsT. PLoS Pathogens 8: e1002719. 2012 Cellular levels and binding of c-di-GMP control subcellular localization and activity of the Vibrio cholerae transcriptional regulator VpsT Lee, B., C. Holkenbrink, A. Treuner-Lange & P.I. Higgs, (2012a) Myxococcus xanthus developmental cell fate production: heterogeneous accumulation of developmental regulatory proteins and reexamination of the role of MazF in developmental lysis. J Bacteriol 194: 3058-3068. 2012a Myxococcus xanthus developmental cell fate production: heterogeneous accumulation of developmental regulatory proteins and reexamination of the role of MazF in developmental lysis Whitney, J.C., K.M. Colvin, L.S. Marmont, H. Robinson, M.R. Parsek & P.L. Howell, (2012) Structure of the Cytoplasmic Region of PelD, a Degenerate Diguanylate Cyclase Receptor That Regulates Exopolysaccharide Production in Pseudomonas aeruginosa. J Biol Chem 287: 23582-23593. 2012 Structure of the Cytoplasmic Region of PelD, a Degenerate Diguanylate Cyclase Receptor That Regulates Exopolysaccharide Production in Pseudomonas aeruginosa Krasteva, P.V., K.M. Giglio & H. Sondermann, (2012) Sensing the messenger: The diverse ways that bacteria signal through c-di-GMP. Protein Sci. 21: 929-948. 2012 Sensing the messenger: The diverse ways that bacteria signal through c-di-GMP Chen, Y., Y. Chai, J.H. Guo & R. Losick, (2012) Evidence for cyclic di-GMP-mediated signaling in Bacillus subtilis. J Bacteriol 194: 5080-5090. 2012 Evidence for cyclic di-GMP-mediated signaling in Bacillus subtilis Black, W.P. & Z. Yang, (2004) Myxococcus xanthus chemotaxis homologs DifD and DifG negatively regulate fibril polysaccharide production. J Bacteriol 186: 1001- 1008. 2004 Myxococcus xanthus chemotaxis homologs DifD and DifG negatively regulate fibril polysaccharide production Steiner, S., C. Lori, A. Boehm & U. Jenal, (2013) Allosteric activation of exopolysaccharide synthesis through cyclic di-GMP-stimulated protein-protein interaction. EMBO J 32: 354-368. 2013 Allosteric activation of exopolysaccharide synthesis through cyclic di-GMP-stimulated protein-protein interaction Shanahan, C.A. & S.A. Strobel, (2012) The bacterial second messenger c-di-GMP: probing interactions with protein and RNA binding partners using cyclic dinucleotide analogs. Organic & biomolecular chemistry 10: 9113-9129. 2012 The bacterial second messenger c-di-GMP: probing interactions with protein and RNA binding partners using cyclic dinucleotide analogs Kazmierczak, B.I., M.B. Lebron & T.S. Murray, (2006) Analysis of FimX, a phosphodiesterase that governs twitching motility in Pseudomonas aeruginosa. Mol Microbiol 60: 1026-1043. 2006 Analysis of FimX, a phosphodiesterase that governs twitching motility in Pseudomonas aeruginosa Vorobiev, S., H. Neely, B. Yu, J. Seetharaman, R. Xiao, T. Acton, G. Montelione & J. Hunt, (2012) Crystal structure of a catalytically active GG(D/E)EF diguanylate cyclase domain from Marinobacter aquaeolei with bound c-di-GMP product. J Struct Funct Genomics 13: 177-183. 2012 Crystal structure of a catalytically active GG(D/E)EF diguanylate cyclase domain from Marinobacter aquaeolei with bound c-di-GMP product Christen, M., H.D. Kulasekara, B. Christen, B.R. Kulasekara, L.R. Hoffman & S.I. Miller, (2010) Asymmetrical Distribution of the Second Messenger c-di-GMP upon Bacterial Cell Division. Science 328: 1295-1297. 2010 Asymmetrical Distribution of the Second Messenger c-di-GMP upon Bacterial Cell Division Friedrich, C., I. Bulyha & L. Sogaard-Andersen, (2014) Outside-in assembly pathway of the type IV pilus system in Myxococcus xanthus. J Bacteriol 196: 378-390. 2014 Outside-in assembly pathway of the type IV pilus system in Myxococcus xanthus Chen, Z.H. & P. Schaap, (2012) The prokaryote messenger c-di-GMP triggers stalk cell differentiation in Dictyostelium. Nature 488: 680-683. 2012 The prokaryote messenger c-di-GMP triggers stalk cell differentiation in Dictyostelium Siewering, K., S. Jain, C. Friedrich, M.T. Webber-Birungi, D.A. Semchonok, I. Binzen, A. Wagner, S. Huntley, J. Kahnt, A. Klingl, E.J. Boekema, L. Sogaard-Andersen & C. van der Does, (2014) Peptidoglycan-binding protein TsaP functions in surface assembly of type IV pili. Proc Natl Acad Sci USA 111: E953-961. 2014 Peptidoglycan-binding protein TsaP functions in surface assembly of type IV pili Lombard, V., H.G. Ramulu, E. Drula, P.M. Coutinho & B. Henrissat, (2014) The carbohydrate-active enzymes database (CAZy) in 2013. Nucleic Acids Res 42: D490-D495. 2014 The carbohydrate-active enzymes database (CAZy) in 2013 Kaiser, D., (1979) Social gliding is correlated with the presence of pili in Myxococcus xanthus. Proc Natl Acad Sci USA 76: 5952-5956. 1979 Social gliding is correlated with the presence of pili in Myxococcus xanthus Hodgkin, J. & D. Kaiser, (1977) Cell-to-Cell Stimulation of Movement in Nonmotile Mutants of Myxococcus. Proc Natl Acad Sci USA 74: 2938-2942. 1977 Cell-to-Cell Stimulation of Movement in Nonmotile Mutants of Myxococcus Cohen, D., U. Mechold, H. Nevenzal, Y. Yarmiyhu, T.E. Randall, D.C. Bay, J.D. Rich, M.R. Parsek, V. Kaever, J.J. Harrison & E. Banin, (2015) Oligoribonuclease is a central feature of cyclic diguanylate signaling in Pseudomonas aeruginosa. Proc Natl Acad Sci USA 112: 11359-11364. 2015 Oligoribonuclease is a central feature of cyclic diguanylate signaling in Pseudomonas aeruginosa Orr, M.W., G.P. Donaldson, G.B. Severin, J. Wang, H.O. Sintim, C.M. Waters & V.T. Lee, (2015) Oligoribonuclease is the primary degradative enzyme for pGpG in Pseudomonas aeruginosa that is required for cyclic-di-GMP turnover. Proc Natl Acad Sci USA 112: E5048-5057. 2015 Oligoribonuclease is the primary degradative enzyme for pGpG in Pseudomonas aeruginosa that is required for cyclic-di-GMP turnover Chan, C., R. Paul, D. Samoray, N.C. Amiot, B. Giese, U. Jenal & T. Schirmer, (2004) Structural basis of activity and allosteric control of diguanylate cyclase. Proc. Natl. Acad. Sci. USA 101: 17084-17089. 2004 Structural basis of activity and allosteric control of diguanylate cyclase Yang, Z., X. Ma, L. Tong, H.B. Kaplan, L.J. Shimkets & W. Shi, (2000) Myxococcus xanthus dif genes are required for biogenesis of cell surface fibrils essential for social gliding motility. J Bacteriol 182: 5793-5798. 2000 Myxococcus xanthus dif genes are required for biogenesis of cell surface fibrils essential for social gliding motility Sun, J., A. Hesketh & M. Bibb, (2001) Functional analysis of relA and rshA, two relA/spoT homologues of Streptomyces coelicolor A3(2). J Bacteriol 183: 3488- 3498. 2001 Functional analysis of relA and rshA, two relA/spoT homologues of Streptomyces coelicolor A3(2) Guzzo, C.R., G. Dunger, R.K. Salinas & C.S. Farah, (2013) Structure of the PilZ– FimXEAL–c-di-GMP complex responsible for the regulation of bacterial type IV pilus biogenesis. J Mol Biol 425: 2174-2197. 2013 Structure of the PilZ– FimXEAL–c-di-GMP complex responsible for the regulation of bacterial type IV pilus biogenesis The nucleotide-based second messenger bis-(3’-5’)-cyclic dimeric GMP (c-di-GMP) is involved in regulating a plethora of processes in bacteria that are typically associated with lifestyle changes. Myxococcus xanthus undergoes major lifestyle changes in response to nutrient availability with the formation of spreading colonies in the presence of nutrients and spore-filled fruiting bodies in the absence of nutrients. Here, we investigated the function of c-di-GMP in M. xanthus. We show that this bacterium synthesizes c-di-GMP. Manipulation of the cellular c-di-GMP level by expression of either an active, heterologous diguanylate cyclase or an active, heterologous phosphodiesterase in vegetative cells caused defects in type IV pili (T4P)-dependent motility whereas gliding motility was unaffected. An increased level of c-di-GMP caused reduced transcription of the pilA gene that encodes the major pilin of T4P, reduced assembly of T4P and altered cell agglutination whereas a decreased level of c-di-GMP caused altered cell agglutination. The systematic inactivation of the 24 genes in M. xanthus encoding proteins containing GGDEF, EAL or HD-GYP domains, which are associated with c-di-GMP synthesis, degradation or binding, identified three genes encoding proteins important for T4P-dependent motility. These three proteins named DmxA, TmoK and SgmT all contain a GGDEF domain. Purified DmxA had diguanylate cyclase activity whereas the TmoK and SgmT (both hybrid histidine protein kinases) did not have diguanylate cyclase activity. During starvation, the c-di-GMP level in M. xanthus increases significantly. Manipulation of this level revealed that a low c-di-GMP level negatively affects the developmental program while an increased level does not interfere with development. Moreover, among the 24 genes encoding proteins containing GGDEF, EAL or HD-GYP domains, we identified two which are specifically involved in development: pmxA and dmxB. pmxA codes for an enzymatically active phosphodiesterase with an HD-GYP domain. dmxB codes for a developmentally induced, enzymatically active diguanylate cyclase. DmxB is essential for the increased c-di-GMP level and regulates exopolysaccharide accumulation during starvation. Our results show that c-di-GMP acts as an important signaling molecule during M. xanthus development, and suggest a model in which a minimal threshold level of c-di-GMP is essential for the successful progression and completion of the developmental program. Additionally, candidates for c-di-GMP effectors in M. xanthus were identified using a capture compound mass spectrometry approach. Some of the candidates were confirmed to bind c-di-GMP in vitro and deletion mutants for genes encoding those proteins were characterized in terms of T4P-dependent motility and development. Regulation durch cyclisches-di-GMP in Myxococcus xanthus urn:nbn:de:hebis:04-z2016-01015 http://dx.doi.org/10.17192/z2016.0101 opus:6616 2016-04-14 Regulation by cyclic di-GMP in Myxococcus xanthus 2016-03-18 Der nukleotid-basierte, sekundäre Botenstoff bis-(3‘-5‘)-cyclic GMP (c-di-GMP) ist an einer Vielzahl von regulatorischen Prozessen im Zusammenhang mit Veränderungen des Lebenszyklusses in Bakterien beteiligt. Myxococcus xanthus reagiert entsprechend der Nährstoffverfügbarkeit in seiner Umgebung. Bei ausreichenden Nährstoffen bildet M. xanthus sich ausbreitende Kolonien. Unter nahrungslimitierenden Bedingungen hingegen werden mit Sporen gefüllte Fruchtkörper geformt. In dieser Arbeit wurde die Funktion von c-di-GMP in M. xanthus untersucht. M. xanthus kann c-di-GMP produzieren. Die Manipulation der zellulären c-di-GMP Konzentration durch Expression einer heterologen, aktiven Diguanylatzyklase oder Phosphodiesterase in lebenden Zellen führte zu einem Defekt der „type-IV-pili“ (T4P) abhängigen Beweglichkeit. Die Gleitbewegung von M. xanthus hingegen blieb dadurch unberührt. Eine erhöhte Konzentration von c-di-GMP reduzierte die Transkription des pilA Genes, welches für das wichtigste Pilin des T4P codiert, reduzierte das Vorkommen von T4P generell und veränderte die Zellagglutination. Ein niedriges Niveau von c-di-GMP führte lediglich zu veränderter Zellagglutination. Die systematische Inaktivierung von 24 Genen in M. xanthus, welche für Proteine mit GGDEF, EAL oder HD-GYP Domänen kodieren, die im Zusammenhang mit der Synthetisierung, dem Abbau oder dem Binden von c-di-GMP stehen, identifizierte drei Gene, die wichtig für die T4P abhängige Bewegung sind. Die dazugehörigen Proteine DmxA, TmoK und SgmT enthalten alle eine GGDEF Domäne. DmxA besitzt Diguanylatzyklaseaktivität, TmoK und SgmT (beide Hybrid Histidinkinasen) zeigen keine Diguanylatzyklaseaktivität in vitro. Die Konzentration von c-di-GMP steigt während nahrungslimitierenden Bedingungen signifikant an. Artifiziell herbeigeführtes niedriges c-di-GMP Niveau beeinflusst das Entwicklungsprogramm, hohes jedoch nicht. Zudem konnten wir aus den 24 Genen, die für Proteine mit GGDEF, EAL und HD-GYP Domänen kodieren, zwei Gene identifizieren, welche spezifisch im Entwicklungsprogramm von M. xanthus involviert sind: pmxA und dmxB. pmxA kodiert für eine enzymatisch aktive Phosphodiesterase mit einer HD-GYP-Domäne. dmxB kodiert für eine im Entwicklungsprogramm induzierte, enzymatisch aktive Diguanylatzyklase. DmxB ist essentiell um ein erhöhtes c-di-GMP Niveau in den Zellen aufrechtzuerhalten und reguliert außerdem Exopolysaccharide während des Nährstoffmangels. Unsere Resultate zeigen, dass c-di-GMP ein wichtiges Signalmolekül im Entwicklungsprogramm von M. xanthus ist und weist auf ein Model hin, in dem ein minimaler Schwellenwert an c-di-GMP Konzentration erreicht sein muss, um ein erfolgreiches Fortschreiten des Entwicklungsprogrammes zu gewährleisten. Zusätzlich konnten wir c-di-GMP spezifische Effektormoleküle mit Hilfe von Massenspektrometrie identifizieren und teilweise charakterisieren. Für einige dieser Kandidaten konnte bestätigt werden, dass sie in vitro c-di-GMP binden und die Deletionsmutanten der korrespodierenden Gene wurden hinsichtlich ihrer Fähigkeit des T4P abhängigen Beweglichkeit und ihres Entwicklungsprogrammes charakterisiert. Skotnicka, Dorota Skotnicka Dorota ths Prof. Dr. Søgaard-Andersen Lotte Søgaard-Andersen, Lotte (Prof. Dr.) Philipps-Universität Marburg
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