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|Title:||UNDERSTANDING THE ROLE OF RNASE L IN THE INNATE IMMUNE RESPONSE TO DOUBLE STRANDED RNA|
|Contributors:||Molecular Biology Department|
|Publisher:||Princeton, NJ : Princeton University|
|Abstract:||Mammalian cells use two central strategies to fight against a pathogenic signature like dsRNA (double stranded RNA). They i) secrete interferons and ii) arrest global protein synthesis due to regulated RNA decay caused by the 2-5A-RNase L axis of innate immunity. We have used X-ray crystallography, recombinant protein engineering, biochemistry, RNA and cell biology to understand the role of RNase L in the innate immune response to self and non-self dsRNA. When cells are challenged with non-self dsRNA mimicking viral infections, interferon proteins bypass RNase L mediated global translation arrest. This work enabled by a nature inspired 2-5A biosensor reveals a fundamental mechanism by which 2-5A-RNase L axis reprograms host translation to prioritize synthesis of defense proteins. On the other hand, when self dsRNA accumulates in cells, RNase L program is activated without an interferon response. We determine the molecular basis for this paradoxical lack of interferon responses and reveal a fundamental mechanism that cells employ to maintain intracellular dsRNA load. To summarize, this thesis examines RNase L biology in the context of interferon signaling and offers new insights into its role as a sensor of self and non-self dsRNA.|
|Alternate format:||The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog: catalog.princeton.edu|
|Type of Material:||Academic dissertations (Ph.D.)|
|Appears in Collections:||Molecular Biology|
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