CRM1-dependent nuclear export of dengue virus type 2 NS5

The dengue virus multidomain RNA polymerase NS5 has been observed in the nucleus in mammalian infected cell systems. We previously showed that NS5 nuclear localization is mediated by two nuclear targeting signals within the NS5 interdomain region that are recognized by distinct members of the importin superfamily of intracellular transporters. Intriguingly, we have recently found that NS5 also possesses the ability to be exported from the nucleus by the importin family member CRM1 (exportin 1) both in Vero cells transfected to express NS5, and in dengue virus type 2 infected Vero cells, based on use of the CRM1-specific inhibitor leptomycin B (LMB). LMB treatment of Vero cells resulted in increased nuclear accumulation in both systems, and interestingly in the latter, resulted in an alteration in the kinetics of virus production. Our results imply that subcellular trafficking of NS5 at particular times in the infectious cycle may be central to the kinetics of virus production; perturbing this trafficking may represent a viable approach to develop new antiviral therapeutics.