Publikationsserver der Universitätsbibliothek Marburg
Titel:Immunerkennung endogener RNA-Liganden
Autor:Jung, Stephanie
Weitere Beteiligte: Bauer, Stefan (Prof. Dr.)
Veröffentlicht:2014
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0647
URN: urn:nbn:de:hebis:04-z2014-06474
DOI: https://doi.org/10.17192/z2014.0647
DDC:610 Medizin
Titel (trans.):Immunorecognition of endogenous RNA ligands
Publikationsdatum:2014-10-14
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
modification, 45S rRNA, RIG I, TLR8, RIG I, TLR8, RNase A, RNase L, RNase A, 45S rRNA, Modifikationen, ITS2, ITS2, RNase L

Zusammenfassung:
Das angeborene Immunsystem verfügt über eine Vielzahl keimbahnkodierter Rezeptoren, die pathogenspezifische Muster erkennen und so eine Immunantwort auslösen können. Verantwortlich für die Detektion doppelsträngiger RNA im Zytoplasma ist die Familie der RIG I ähnlichen Rezeptoren, zu der u.a. RIG I und MDA5 gehören; im Endosomen wird doppel- und einzelsträngige RNA durch die Toll-ähnlichen Rezeptoren („Toll like receptors“, TLRs) 3, 7 und 8 erkannt. Diese Rezeptoren können unter physiologischen Bedingungen anhand von Struktur und Modifikationen zwischen zelleigener und zellfremder RNA unterscheiden, unter pathologischen Bedingungen kann es aber auch zu einer Erkennung körpereigener RNA kommen. Der Hauptteil dieser Arbeit beschäftigt sich mit der Erkennung zelleigener RNA im Zytoplasma. Während einer Virusinfektion kann doppelsträngige virale RNA nicht nur direkt durch die RIG I ähnlichen Rezeptoren erkannt werden, sondern auch indirekt über 2‘5‘ Oligoadenylat-aktivierte RNase L aktivieren. Dies führt zum Schneiden zelleigener RNA, wobei die gebildeten Fragmente wiederum von keimbahn-kodierten Rezeptoren erkannt werden. Diese Verstärkung des Gefahrensignals nimmt eine grundlegende Rolle in der Virusabwehr ein. Im Rahmen dieser Arbeit konnte gezeigt werden, dass die Erkennung zelleigener RNase-generierter RNA-Fragmente ausschließlich über RIG I verläuft. Die Existenz spezifischer endogener RIG I Liganden wurde belegt und die Sequenzen der betreffenden Fragmente wurden mittels Next Generation Sequencing ermittelt. Hierbei handelt es sich um Strukturen aus der 28S rRNA und der ITS2, einem Prozessierungsprodukt der 45S rRNA. Der spezifische RIG I aktivierende Effekt dieser Sequenzen konnte in verschiedenen Stimulationsexperimenten nachgewiesen werden. Interessanterweise tragen die endogenen stimulatorischen RNA-Spezies im Gegensatz zum Prototyp eines RIG I Liganden kein 5' Triphosphat, sondern ein 3' Monophosphat, auch weisen sie keine typische Basenzusammensetzung mit hohem Uridingehalt auf. Stattdessen werden die außergewöhnlich GC-reichen Sequenzen vermutlich aufgrund ihrer Doppelsträngigkeit und einer Ringstruktur nahe der Schnittstelle von RIG I erkannt. Die besondere Bedeutung dieser Sequenzen wird durch die evolutionäre Konservierung dieser Strukturen belegt, auch könnten sie nicht nur eine Funktion in der Virusabwehr, sondern auch als Tumorsupressor haben. Die intrazelluläre Generierung immunstimulatorischer RNA-Spezies erfolgt nicht nur über die virusinduzierte RNase L, sondern auch über eine artifiziell in die Zelle transfizierte RNase A. Dies eröffnet die Möglichkeit zur Etablierung von RNase A als neue Adjuvansspezies. Im zweiten Teil dieser Arbeit wurde untersucht, welchen Einfluss verschiedene Modifikationen des 18S rRNA Abkömmlings RNA63 auf dessen Erkennung durch die endosomalen TLRs 7 und 8 haben. Eine nichtmodifizierte RNA63 und solche mit einer 2'-O-Deoxy- oder Fluorgruppe werden sowohl durch TLR7 als auch durch TLR8 erkannt. Durch eine 2'-O-Methylierung allerdings lässt sich die Erkennung der RNA63 durch TLR7 hemmen, nicht aber die Erkennung durch TLR8. Somit handelt es sich bei 2'-methylierter RNA63 um einen spezifischen TLR8-aktivierenden Liganden.

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