WNV NS4B-Induced Membrane Structures as a Potential Target for Therapeutic Drugs

Date/Time: 05 October 2011, 12:00 PM - 1:00 PM
Speaker: Pakieli H. Kaufusi, Ph.D.
Speaker Affiliation: Junior Researcher, Department of Tropical Medicine, Medical Microbiology and Pharmacology
Venue: John A. Burns School of Medicine, Kaka’ako, MEB Auditorium (Room 315)

For more info: Cori Watanabe (808) 692-1654
Description: Flavivirus replication occurs in specialized virus-induced membrane structures (IMS), the origins of which are quite variable. Our long-term goal is to elucidate the regulatory mechanisms controlling the formation of IMS as a prerequisite to the development of a therapeutic approach to disrupt the disease process. Our central hypothesis is that West Nile virus (WNV) nonstructural (NS) 4B (NS4B) protein is a major regulatory initiator controlling IMS formation. In our studies, we demonstrate that WNV strain NY99 remodels the ER membrane, similar to dengue virus (DENV), and possibly recruits the cis-Golgi components to generate IMS organelles. Markers for the ER and cis-Golgi but not the ER-Golgi intermediate compartments, the trans-Golgi, or early endosomes redistribute to WNV strain NY99 IMS. Additionally, NS proteins 4A and 4B lacking the 2K-signal sequence are responsible for ER-derived IMS. Moreover, the central region of NS4B is vital for IMS formation. Unlike other flaviviruses, maturation of WNV strain NY99 NS4A and NS4B via NS4A-2K-4B processing occurs without the viral protease in HEK293 cells. Collectively, these data suggest that NS4A and NS4B are critically important for WNVNY99 IMS formation. This newfound knowledge will significantly impact the development of therapeutic interventions for WNV and other re-emerging mosquito-borne pathogens.