New Insights into Flavivirus Nonstructural Protein 5

Disease caused by flavivirus infections is an increasing world health problem. Flavivirus nonstructural protein 5 (NS5) possesses enzymatic activities required for capping and synthesis of the viral RNA genome and is essential for virus replication. NS5 is comprised of two domains. The N-terminal domain binds GTP and can perform two biochemically distinct methylation reactions required for RNA cap formation. The C-terminal domain contains RNA-dependent RNA polymerase activity. As such, NS5 is an interesting target against which antiviral drugs could be developed and research toward this goal has accelerated our understanding of NS5 structure and function in recent years. The production and purification of recombinant versions of either the full-length NS5 or the two individual NS5 domains has led to detailed enzymatic studies on NS5 and the determination of structures of the two NS5 domains. In turn, studies using a combination of structural, biochemical, and reverse genetic approaches are revealing how NS5 performs its multifunctional roles in genome replication. Aside from its localization in the membrane-bound replication complex, NS5 can be found free in the cytoplasm and for some flaviviruses in the nucleus of virus-infected cells. NS5 is phosphorylated which may potentially regulate NS5 function and trafficking. Recently, NS5 of a number of flaviviruses has been shown to interact with cellular pathways involved in the host immune response, suggesting that NS5 may play a role in viral pathogenesis. This chapter reviews recent advances in our understanding of the multifunctional roles played by NS5 in the virus lifecycle.