Although all established functions of dengue virus non-structural protein 5 (NS5) occur in the cytoplasm, its nuclear localization, mediated by dual nuclear localization sequences (NLSs), is essential for virus replication. Here we determine the mechanism by which NS5 can localize in the cytoplasm to perform its role in replication, establishing for the first time that it is able to be exported from the nucleus by the exportin, CRM1, and hence can shuttle between the nucleus and cytoplasm. We define the nuclear export sequence (NES) responsible to be residues 327-343 and confirm interaction of NS5 and CRM1 by pull-down. Significantly, greater nuclear accumulation of NS5 during infection due to CRM1 inhibition coincided with altered kinetics of virus production and decreased induction of the antiviral chemokine interleukin-8 (IL-8). This is the first report of a NES within NS5 for any member of the flavivirus genus; because of its high conservation within the genus, it may represent a target for the treatment of diseases caused by several medically-important flaviviruses.
Rawlinson, S. M., Pryor, M. J., Wright, P. J., & Jans, D. A. (2009). CRM1-mediated nuclear export of dengue virus RNA polymerase NS5 modulates interleukin-8 induction and virus production. The Journal of Biological Chemistry, 284(23), 15589 - 15597. https://doi.org/10.1074/jbc.M808271200