A comparative analysis of the subcellular trafficking of the NS5 protein of dengue and West Nile viruses
Flaviviruses are significant pathogens that cause considerable morbidity and mortality all around the globe. Despite intense research in the past two decades, a considerable part of the life cycle and pathogenesis is still poorly understood. NS5 is a highly conserved and multifunctional protein that contains the viral polymerase and the methyltransferase enzymes. Despite the conservation in primary amino acid sequence and the similarities in the crystal structures of the domains predicted to be involved in its trafficking, the NS5 protein from different flaviruses exhibits distinct subcellular localizations. In this study we compare and dissect the apparatus responsible for these disparate nucleocytoplasmic distributions of the West Nile virus (WNV) and the dengue virus 2 (DENV2) NS5 proteins. Through genetic, cellular and biochemical techniques we define a three-component trafficking pathway for flavivirus NS5, namely a nuclear localization signal, an overlapping membrane association region and a conserved arginine switch that can override and reverse the nucleocytoplasmic distribution of NS5. We show that despite differences, the basic components of this trafficking pathway are conserved and the viruses have evolved to tweak these features to obtain a unique outcome probably to suit their survival. ^
David A. Sanders, Purdue University, Richard J. Kuhn, Purdue University.
Biology, Molecular|Biology, Virology