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Identifizierung Neuer Nicht-Kodierender Rnas in Xanthomonas Campestris Pv

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Identifizierung Neuer Nicht-Kodierender Rnas in Xanthomonas Campestris Pv Identifizierung neuer nicht-kodierender RNAs in Xanthomonas campestris pv. vesicatoria und funktionelle Charakterisierung der regulatorischen RNA sX13 Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) der Naturwissenschaftlichen Fakultät I – Biowissenschaften – der Martin-Luther-Universität Halle-Wittenberg, vorgelegt von Herrn Cornelius Schmidtke geb. am 15.05.1982 in Jena Gutachter: Prof. Dr. U. Bonas Prof. Dr. G. Sawers Prof. Dr. W. Hess Verteidigung: 29.04.2014 I Teile dieser Arbeit wurden in Fachzeitschriften publiziert: Schmidtke, C., Findeiß, S., Sharma, C.M., Kuhfuss, J., Hoffmann, S., Vogel, J., Stadler, P.F. and Bonas, U. (2012) Genome-wide transcriptome analysis of the plant pathogen Xanthomonas identifies sRNAs with putative virulence functions. Nucleic Acids Res., 40, 2020-2031. Findeiß, S., Schmidtke, C., Stadler, P.F. and Bonas, U. (2010) A novel family of plasmid- transferred anti-sense ncRNAs. RNA Biol, 7, 120-124. Schmidtke, C., Abendroth, U., Brock, J., Serrania, J., Becker, A. and Bonas, U. (2013) Small RNA sX13: a multifaceted regulator of virulence in the plant pathogen Xanthomonas. PLoS Pathog., 9, e1003626. II Zusammenfassung Das Gram-negative pflanzenpathogene γ-Proteobakterium Xanthomonas campestris pv. vesicatoria ist der Erreger der bakteriellen Fleckenkrankheit auf Paprika und Tomate. Die Kenntnis bakterieller Faktoren, die zur Infektion von Wirtspflanzen beitragen, war zu Beginn dieser Arbeit auf Proteine begrenzt, wohingegen die Rolle nicht-kodierender RNAs in der Virulenz von Xanthomonas Spezies unbekannt war. Mittels eines cDNA-Sequenzieransatzes, welcher die Unterscheidung von Primärtranskripten und prozessierten RNAs ermöglicht, wurden 1.421 potentielle Transskriptionsstartpositionen sowie abundante nicht-kodierende RNAs in X. campestris pv. vesicatoria Stamm 85-10 identifiziert. Insgesamt wurden 24 potentiell regulatorische RNAs experimentell bestätigt, von denen drei (PtaRNA1, sX12 und sX13) näher untersucht wurden. Bioinformatische Analysen deuten darauf hin, dass der ptaRNA1 (‚plasmid-transferred antisense RNA 1‘) Lokus durch horizontalen Gentransfer verbreitet wird und lassen vermuten, dass die PtaRNA1 antisense RNA die Synthese eines potentiell toxischen Proteins unterdrückt. Acht der in dieser Arbeit identifizierten nicht-kodierenden RNAs, einschließlich sX12, sind mit dem Typ III Sekretionssystem, einem essentiellen Pathogenitätsfaktor von X. campestris pv. vesicatoria, ko-reguliert. Durch genetische Analysen konnte nachgewiesen werden, dass sX12 die Virulenz von X. campestris pv. vesicatoria fördert. In dieser Arbeit wurde zudem die konstitutiv exprimierte und abundante sX13 RNA als neuartiger Virulenzfaktor von X. campestris pv. vesicatoria identifiziert. sX13 fördert die Expression von Komponenten und Substraten des Typ III Sekretionssystems und trägt zum bakteriellen Wachstum in Kultur bei. ‚Microarray‘ Analysen ergaben ein großes sX13 Regulon und lassen vermuten, dass sX13 zur Adaption von X. campestris pv. vesicatoria an sich verändernde Umweltbedingungen beiträgt. sX13 hemmt die Expression des RNA-Bindeproteins Hfq, welches in zahlreichen Bakterien für die Aktivität regulatorischer RNAs essentiell ist und zur Virulenz pathogener Bakterien beiträgt. Die Ergebnisse deuten darauf hin, dass sX13 Hfq-unabhängig agiert und dass hfq für die Virulenz von X. campestris pv. vesicatoria entbehrlich ist. Strukturanalysen von sX13 sowie Deletions- und Komplementationsexperimente ergaben, dass sX13 drei ‚Stem-Loop‘ Strukturen mit ‚C‘-reichen Loops aufweist, welche in unterschiedlichem Maße zur Virulenz von X. campestris pv. vesicatoria beitragen. Mittels eines GFP-Reportersystems wurde nachgewiesen, dass ‚C‘-reiche sX13 Loops und ‚G‘-reiche Motive in potentiellen Ziel-mRNAs für die sX13-abhängige Repression der Proteinsynthese essentiell sind. III Summary The Gram-negative plant-pathogenic γ-proteobacterium Xanthomonas campestris pv. vesicatoria is the causal agent of bacterial spot disease on pepper and tomato. At the beginning of this study, the knowledge of bacterial factors, which contribute to the infection of host plants, was limited to proteins, whereas the role of noncoding RNAs in the virulence of Xanthomonas species was unknown. Using a cDNA-sequencing approach, which allows distinguishing unprocessed and processed RNAs, 1,421 putative transcription start sites and abundant noncoding RNAs were identified in X. campestris pv. vesicatoria strain 85-10. In total, 24 putative regulatory RNAs were experimentally verified, three of which (PtaRNA1, sX12 and sX13) were analyzed in more detail. Bioinformatic analyses suggest that the ptaRNA1 (‘plasmid-transferred antisense RNA 1’) locus is transferred via horizontal gene transfer and further indicate that the PtaRNA1 antisense RNA represses the synthesis of a presumably toxic protein. Eight of the identified noncoding RNAs, including sX12, are co-regulated with the type III secretion system, which constitutes an essential pathogenicity factor of X. campestris pv. vesicatoria. Genetic analyses showed that sX12 contributes to virulence of X. campestris pv. vesicatoria. Furthermore, this work revealed that the constitutively expressed and abundant sX13 RNA represents a novel virulence factor of X. campestris pv. vesicatoria. sX13 promotes the expression of components and substrates of the type III secretion system and contributes to bacterial growth in culture. Microarray analyses revealed a large sX13 regulon and suggest that sX13 contributes to environmental adaptation of X. campestris pv. vesicatoria. sX13 inhibits the expression of the RNA-binding protein Hfq, which is essential for the activity of regulatory RNAs in many bacteria and contributes to virulence of pathogenic bacteria. The data suggest that sX13 acts Hfq-independently. Furthermore, hfq is presumably not involved in virulence of X. campestris pv. vesicatoria. Structure analyses of sX13 and deletion and complementation experiments revealed that sX13 consists of three stem-loops with ‘C’-rich loops, which differentially contribute to virulence of X. campestris pv. vesicatoria. Using a GFP-reporter system, both the ‘C’-rich sX13 loops and ‘G’-rich motifs in presumed target mRNAs were shown to be essential for the sX13-dependent repression of protein synthesis. IV Danksagung Mein besonderer Dank gebührt allen, die an mich geglaubt haben, allen voran Frau Prof. Dr. Ulla Bonas für die Bereitstellung dieses hochinteressanten und anspruchsvollen Forschungsthemas, die fruchtbaren Diskussionen und ihr stetiges Vertrauen in meine Fähigkeiten. Zudem danke ich allen Kooperationspartnern, insbesondere Sven Findeiß, Juliane Brock und Ulrike Abendroth, die maßgeblich zum Erfolg dieser Arbeit beigetragen haben. Für die schöne Zeit, den regen Gedankenaustausch und die freundliche Arbeitsatmosphäre bedanke ich mich bei den Mitgliedern des Labors 215, Evelyn Löschner, Ulrike Abendroth, Juliane Brock, Christine Wagner und Johannes Stuttmann, sowie bei allen Mitgliedern der Arbeitsgruppe Bonas. Carola Kretschmer, Hannelore Espenhahn und Marina Schulze danke ich für die hervorragende technische Assistenz und Bianca Rosinsky für ihren grünen Daumen. Ein herzlicher Dank gilt Heike Berndt, Daniela Büttner, Steve Schulz, Sebastian Schulze, Tom Schreiber und Oliver Müller für die pausenfüllenden Diskussionen und Hilfe in allen Lebenslagen. Simone Hahn und Robert Szczesny danke ich für wahre Freundschaft. Mein aufrichtiger Dank gilt meiner Familie für ihre bedingungslose Unterstützung und meiner Frau Katja, ohne deren Liebe, Geduld und Zuspruch diese Arbeit vermutlich nicht möglich gewesen wäre. Danke! V Inhaltsverzeichnis Zusammenfassung ................................................................................................................................ II Summary .............................................................................................................................................. III Danksagung .......................................................................................................................................... IV Inhaltsverzeichnis ................................................................................................................................. V Abbildungsverzeichnis ...................................................................................................................... VII Abkürzungsverzeichnis .................................................................................................................... VIII 1. Einleitung ....................................................................................................................................... 1 1.1. Experimentelle Identifizierung regulatorischer RNAs ............................................................ 1 1.2. Identifizierung von Transkriptionsstarts mittels dRNA-Seq ................................................... 2 1.3. Funktionen und Mechanismen RNA-vermittelter Regulation ................................................. 3 1.3.1. Riboswitches und RNA-Thermometer ............................................................................ 3 1.3.2. RNA-vermittelte Modulation der Proteinaktivität ........................................................... 4 1.3.3. Cis-kodierte antisense RNAs ........................................................................................... 5 1.3.4. Trans-kodierte RNAs .....................................................................................................
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