Nuclear role of Dengue proteins in infection

Background Nuclear transport is central to eukaryotic cell processes such as signal transduction and differentiation, where changes in transcription within the nucleus are mediated by transcription factors which gain access to the nucleus through cellular transporters called importins (IMPs). IMPs are also critical in oncogenesis, whereby their misregulation can cause mislocalisation of transcription factors. Finally, nuclear transport is critical in viral infection, where viruses utilise or disrupt mechanisms of the infected host cell to ensure the precise subcellular localisation of critical viral proteins, as well as to mislocalise host proteins, resulting in increased virus replication and inhibition of host anti-viral responses. We focus on viruses of medical significance (Dengue, HIV etc.) and cancer as model systems to study the importance of nuclear transport during infection and tumorigenesis. The results will identify new targets for therapeutic intervention and help develop novel urgently required anti-viral/anti-cancer agents. Project The NS5 gene product from the causative agent of dengue fever, dengue virus (DENV), localises predominantly in the nucleus, even though its function in virus replication is in the cytoplasm. We have shown that NS5’s trafficking into and out of the nucleus is essential to virus replication, and that inhibitors of NS5 nuclear accumulation can block DENV infection. This project examines interactions of NS5 with host-cell proteins within the nucleus and their importance to infection, as well as developing small molecule inhibitors of NS5 nuclear import to stop DENV infection.