UNDERSTANDING THE ROLE OF RNASE L IN THE INNATE IMMUNE RESPONSE TO DOUBLE STRANDED RNA

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.