Dokument

Zusammenfassung:
Das Nukleoprotein der Arenaviren erfüllt zentrale Aufgaben im viralen Replikationszyklus. Dazu gehört die Enkapsidierung des viralen Genoms und die Regulation von Transkription und Replikation sowie die Interaktion mit dem Matrixprotein und die Inhibition der Typ I Interferon-Antwort. Über die Homo-Oligomerisierung des Nukleoproteins, ihre Bedeutung für diese vier Aufgaben sowie die hierfür notwendigen Domänen innerhalb des Nukleoproteins war bisher nichts bekannt. In der vorliegenden Arbeit wurde gezeigt, dass sich das Nukleoprotein in Abwesenheit viraler RNA zu symmetrischen, ringförmigen Trimeren zusammenlagert. Die Bildung dieser Trimere ist unabhängig von posttranslationalen Modifikationen und ist innerhalb der Arenaviren konserviert. Mutationsanalysen ergaben, dass Bereiche innerhalb der N- und der C-terminalen Domäne kritisch für die Trimerisierung des Nukleoproteins sind. Darüber hinaus wurde gezeigt, dass die Oligomerisierung des Nukleoproteins eine Grundvorraussetzung für seine Funktion bei der Replikation und Transkription des viralen Genoms ist. Im Gegensatz dazu spielt sie bei der Interaktion des Nukleoproteins mit dem Matrixprotein und für die Fähigkeit des Nukleoproteins zur Inhibition der Typ I Interferon-Antwort keine Rolle. Vermutlich wird das Nukleoprotein der Arenaviren durch Wirtszell-spezifische Proteasen verkürzt. Die dabei entstehenden, großen Spaltfragmente liegen als Monomere vor und könnten in der infizierten Zelle die Funktion als Interferon-Antagonist übernehmen, während ungespaltenes Nukleoprotein für die Replikation, Transkription und Enkapsidierung des viralen Genoms verwendet wird. Das Nukleoprotein sorgt durch seine Interaktion mit dem Matrixprotein für den Einbau des viralen Genoms in neu entstehende Virionen. In dieser Arbeit wurden die dafür verantwortlichen Aminosäurebereiche auf kurze Bereiche innerhalb der C-terminalen Proteindomäne des Nukleoproteins eingegrenzt. Anhand dieser Untersuchungen wurde ein Modell für die Interaktion zwischen dem Nukleoprotein und dem Matrixprotein an der Virusmembran aufgestellt. Vergleichende Studien zwischen den Nukleoproteinen und Matrixproteinen verschiedener Arenaviren ergaben zudem, dass heterotypische Interaktionen nur zwischen dem Nukleoprotein und dem Matrixprotein nahe verwandeter Arenaviren möglich sind. Die Interaktion zwischen dem Nukleoprotein und dem Matrixprotein wurde somit als Faktor identifiziert, der die die Bildung von Arenavirus-Reassortanten stark einschränkt. Insgesamt konnte in dieser Arbeit der Zusammenhang zwischen der Homo-Oligomerisierung und den biologischen Funktionen des Nukleoproteins aufgezeigt werden. Darüber hinaus wurden funktionelle Domänen für die NP-NP-Interaktion und die Interaktion zwischen dem Nukleoprotein und dem Matrixprotein innerhalb des Nukleoproteins identifiziert.

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