Roles of ADAR and RNA editing in host-virus interaction and associated diseases

RNA editing events mediated by the ADAR family proteins constitute an integral step in generating the complexity and diversity of cellular RNA signatures, but the physiological consequences are largely unknown. Interestingly, given its interferon inducibility and previously described function of editing the viral RNA, ADAR1 represents a potentially critical determinant in the host response to viral infection and associated pathophysiology.bOur recent high-throughput sequencing studies unveiled hitherto unrecognized RNA A-to-I(G) editing events on several gene transcripts implicated in the innate antiviral response, implying an ADAR1-based regulatory mechanism that underlies the cellular response to virus intrusion. However, the molecular mechanisms and cellular relevance of such regulatory circuitry are largely unresolved. In particular, what mode of regulation is achieved molecularly, how the genetic information recoding is manifested at the RNA and cellular level, and how this post-transcriptional regulation of innate immunity genes is coordinated with its physiological or pathophysiological roles remain to be answered. In this proposal, we are attempting to outline and execute a set of synergistic experiments to further explore the interplay between RNA editing and innate antiviral mechanism. In Aim 1 we propose a series of functional genomic-based experiments as well as gene expression analysis. The overall goal of Aim 1 is to comprehensively identify the RNA targets of ADAR1 and to pinpoint, among the potential targets, any candidate genes related to innate immunity. The overall goal of Aim 2 is then to characterize the molecular mechanism and biological consequences of editing on the host transcripts. To this end, we will set out to delineate, via a series of biochemical and cell-based assays, the mode of action undertaken by ADAR1. The objective of Aim 3 is to assess the functional outcome of the ADAR1-mediated activity in antiviral response. To this end, we will design cell biological studies to address the impacts of ADAR1 and cellular editing events in virus infection and replication. Overall, these studies will extend our understanding of the cellular role of ADAR1 and the regulation of RNA editing in general, taking it to new levels at which function is explored in a disease context. By establishing the regulatory network of ADAR1 in host-virus interaction and its pathophysiological relevance, these studies may have tremendous potential for the development of new therapeutic schemes for diseases or conditions associated with virus intrusion.

Project ID:PG10401-0062
External Project ID:NHRI-EX104-10321SI