Publikationsserver der Universitätsbibliothek Marburg
Titel:Der Einfluss von N6-Methyladenosin auf die Replikation von Influenzaviren
Autor:Laukemper, Viktoria
Weitere Beteiligte: Bauer, Stefan (Prof. Dr.)
Veröffentlicht:2017
URI:https://archiv.ub.uni-marburg.de/diss/z2017/0752
URN: urn:nbn:de:hebis:04-z2017-07529
DOI: https://doi.org/10.17192/z2017.0752
DDC:610 Medizin
Titel (trans.):The influence of N6-methyladenosine on the replication of influenza viruses
Publikationsdatum:2017-12-14
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:

Zusammenfassung:
RNA-Moleküle verschiedenster Organismen enthalten zahlreiche chemisch modifizierte Nukleoside, deren Funktionen bisher nur zum Teil verstanden sind. In eukaryotischer mRNA ist N6-Methyladenosin (m6A) die am häufigsten vorkommende Modifikation und entsteht durch die Methylierung der Aminogruppe an Position 6 des Ringsystems. Diese wird durch einen Enzymkomplex aus METTL3, METTL14 und WTAP innerhalb der Konsensussequenz [G/A/T][G>A]m6AC[T>A>C] vermittelt. Die Sequenzabfolge GGACT ist dabei das am häufigsten methylierte Motiv. Verschiedene Studien deuten darauf hin, dass m6A verschiedene Schritte des RNA-Metabolismus beeinflusst und damit zahlreiche zelluläre Prozesse regulieren kann. Hierbei wird insbesondere ein Einfluss von m6A auf die Translation, das Spleißen und die Stabilität von RNA diskutiert. Die Effekte von m6A werden in der Zelle durch Bindung verschiedener reader-Proteine aus der hnRNP- und YTH-Proteinfamilie vermittelt. Interessanterweise enthält auch die mRNA verschiedener Viren m6A, aber die Funktion dieser Modifikation für die Virusreplikation und Pathogenese sind noch zu einem großen Teil unverstanden. Ältere Studien deuten darauf hin, dass auch die mRNA von Influenzaviren m6A enthält, wobei die genauen Positionen der Methylierungen nicht bekannt sind. In dieser Arbeit wurde der Einfluss von m6A auf die Replikation des Influenzastammes A/Puerto Rico/8/1934 H1N1 untersucht. Dafür wurden rekombinanten Viren hergestellt, die Mutationen in den m6A-Konsensusmotiven GGACT der viralen NS-, NA- oder HA-mRNA enthielten, sodass an diesen Positionen keine Methylierung mehr stattfinden konnte, gleichzeitig jedoch keine Veränderung der Aminosäuresequenz induziert wurde. Durch Replikationsversuche und Untersuchung der Protein- sowie mRNA-Expression in humanen Zelllinien wurden die Viren charakterisiert und mit Wildtyp(wt)-Viren verglichen. Dabei zeigte sich, dass die Viren mit den mutierten GGACT-Motiven in der HA-mRNA deutlich schlechter replizierten als die wt-Viren und zudem eine reduzierte Expression der HA-mRNA- sowie des HA-Proteins zeigten. Die Mutationen in den GGACT-Motiven der NS- und NA-mRNA hatten hingegen keinen Einfluss auf die Virusreplikation. Um die Beobachtungen aus den Replikationsversuchen auf den Methylierungsstatus der Viren zurückführen zu können, wurden die m6A-Positionen in der mRNA des wt-Virus und des Virus mit den Mutationen in der HA-mRNA mithilfe der Methode des methylated RNA immunoprecipitation with next generation sequencing (MeRIP-Seq) identifiziert. So konnte gezeigt werden, dass die GGACT-Motive der NS- und NA-mRNA des wt-Virus nicht methyliert vorlagen, was die normale Replikationsfähigkeit der entsprechenden Virusmutanten erklärte. Von den GGACT-Motiven in der HA-mRNA des wt-Virus enthielt nur ein einziges eine m6A-Modifikation. Hierbei handelte es sich um das 2. GGACT-Motiv in der HA-mRNA. Diese Methylierung konnte in der mRNA des Virus, bei dem die GGACT-Motive in der HA-mRNA durch Mutationen verändert wurden, nicht mehr identifiziert werden. Replikationsversuche mit Viren, bei denen die GGACT-Motive der HA-mRNA nicht gleichzeitig, sondern einzeln mutiert vorlagen, konnten zeigen, dass die Mutation des 2. GGACT-Motivs zu einer reduzierten Replikationsfähigkeit und zu einer verringerten Expression der HA-mRNA- sowie des HA-Proteins führte. Die reduzierte Replikationsfähigkeit des Virus, welches Mutationen an allen GGACT-Motiven in der HA-mRNA aufwies, konnte damit allein auf die Mutation des 2. GGACT-Motivs und dem damit einhergehenden Verlust der m6A-Modifikation an dieser Position zurückgeführt werden. Durch das MeRIP-Seq konnten weitere m6A-Modifikationen in den mRNAs des NS-, M-, NA-, NP- und HA-Segments nachgewiesen werden, insbesondere in den 5‘- und 3‘-Regionen, deren Funktionen in weiteren Versuchen untersucht werden muss. Der Nachweis einer Influenza-vermittelten Regulation der m6A-assoziierten Proteine sollte Hinweise liefern, durch welche Mechanismen m6A die virale RNA- und Proteinexpression während einer Infektion beeinflusst. Eine Influenza-vermittelte Veränderung der mRNA-Expression von Demethylasen, Methyltransferasen und reader-Proteinen konnte in den verwendeten Zelllinien jedoch nicht gezeigt werden. Aufgrund bisheriger Studien, die auf eine YTHDF2-vermittelte Verstärkung der Proteintranslation von methylierter mRNA hindeuten, wurde auch die Proteinexpression von YTHDF2 in humanen Zellen während einer Influenzainfektion untersucht. Auch hier zeigte sich jedoch keine Veränderung in der Expression. Weitere Versuche werden daher klären müssen, durch welche Mechanismen m6A in der Influenza-mRNA die Proteinexpression und Replikation beeinflusst. Zusammenfassend konnte damit in dieser Arbeit gezeigt werden, dass der Verlust einer m6A-Modifikation in der viralen mRNA zu einer reduzierten Replikationsfähigkeit der Influenzaviren führte. Diese Daten deuten darauf hin, dass die Hemmung der m6A-Modifikation in der Zelle die Replikation der Influenzaviren einschränken könnte und damit das Potential für einen neuen Therapieansatz gegen die Influenzagrippe bietet.

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