Publikationsserver der Universitätsbibliothek Marburg
Titel:Die Phosphorylierung des Ebolavirus VP30 reguliert die virale Transkription und Replikation
Autor:Biedenkopf, Nadine
Weitere Beteiligte: Becker, Stephan (Prof. Dr. )
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2012/0258
DOI: https://doi.org/10.17192/z2012.0258
URN: urn:nbn:de:hebis:04-z2012-02585
DDC: Medizin
Titel (trans.):Phosphorylation of Ebola virus VP30 regulates viral transcription and replication
Publikationsdatum:2012-03-19
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Mononegavirales, RNS-Viren, Replikation, transcription, Ebola-Virus, Nukleokapsidproteine, Transkription, VP30, Ebola virus, VP30, nucleocapsid proteins, replication

Zusammenfassung:
Das Ebolavirus bildet zusammen mit dem Marburgvirus die Familie der Filoviridae, die ein einzelsträngiges nichtsegmentiertes RNA Genom in negativer Orientierung besitzen. Filoviren verursachen schwere hämorrhagische Fieber in Menschen und Affen, weswegen sie als BSL4-Pathogene klassifiziert werden. Die Transkriptions- und Replikationseinheit des Virus bildet der Nukleokapsidkomplex, der sich aus dem RNA-Genom sowie den Nukleokapsidproteinen NP, VP30, VP35 und L zusammensetzt. Dabei agiert VP30 als essentieller Ebolavirus-spezifischer Transkriptionsfaktor, der für die Replikation nicht benötigt wird. Die Aktivität als Transkriptionsfaktor wird über die Phosphorylierung des Proteins reguliert. Nichtphosphoryliertes VP30 unterstützt die Synthese der viralen mRNAs in einem Minigenomsystem, während das phosphorylierte VP30 die Transkription nicht aktivieren kann. Im ersten Teil der vorliegenden Arbeit wurde der Einfluss der VP30 Phosphorylierung auf die Regulation des Übergangs von viraler Transkription zu Replikation untersucht. Dabei stand im Vordergrund der Einfluss der Phosphorylierung auf die Replikation. Mit Hilfe von phospho-mimetischen Mutanten des VP30 konnte gezeigt werden, dass phosphoryliertes VP30 die Replikation fördert, während dephosphoryliertes VP30 einen hemmenden Effekt auf die Replikation besaß. Weiterhin wurde die Interaktion von VP30 mit den anderen Komponenten des Nukleokapsidkomplexes untersucht. Dabei wurde eine bisher unbekannte Interaktion des VP30 mit dem Polymerase Co-Faktor VP35 beschrieben, die vom Phosphorylierungsstatus des VP30 beeinflusst wurde. Möglicherweise führt die phosphorylierungsabhängige Interaktion des VP30 mit VP35 zu einem Ausschluss von VP30 aus einem putativen Transkriptasekomplex und dadurch zur Hemmung der Transkription und Stimulierung der Replikation. Außerdem konnte in der vorliegenden Arbeit gezeigt werden, dass eine dynamische Phosphorylierung des VP30 essentiell für die initialen Schritte der Primären Transkription in frühen Stadien des viralen Lebenszyklus ist. Eine dynamische Phosphorylierung des VP30 an Serinrest 29 war ausreichend für die Generierung eines rekombinanten Ebolavirus mit wildtypischen Eigenschaften. Im Gegensatz dazu ließ sich ein stabiles rekombinantes Virus mit Serinrest 30 als einziger Phosphoakzeptorstelle nicht herstellen und resultierte im Auftreten von kompensatorischen Mutationen innerhalb der VP30 Phosphorylierungsdomäne. Die im Rahmen dieser Arbeit gewonnen Ergebnisse unterstreichen die Bedeutung der VP30 Phosphorylierung für den viralen Replikationszyklus: die dynamische Phosphorylierung des VP30 ist in frühen Stadien des Infektionszyklus für die Primäre Transkription essentiell und besitzt ebenfalls einen Einfluss auf den Übergang von viraler Transkription zu Replikation.

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