Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection

Shuhei Taguwa1, Kevin Maringer2, 5, Xiaokai Li3, Dabeiba Bernal-Rubio2, Jennifer N. Rauch3, Jason E. Gestwicki3, Raul Andino4, Ana Fernandez-Sesma2, Judith Frydman1,

Highlights
•The Hsp70 chaperone network mediates distinct steps of the dengue virus life cycle
•DENV cycle requires Hsp70 for viral entry, RNA replication, and virion production
•Hsp70 function at each step of DENV cycle is specified by different DNAJ proteins
•Drug inhibitor of Hsp70 potently blocks DENV infection in human and mosquito cells

Summary
Viral protein homeostasis depends entirely on the machinery of the infected cell. Accordingly, viruses can illuminate the interplay between cellular proteostasis components and their distinct substrates. Here, we define how the Hsp70 chaperone network mediates the dengue virus life cycle. Cytosolic Hsp70 isoforms are required at distinct steps of the viral cycle, including entry, RNA replication, and virion biogenesis. Hsp70 function at each step is specified by nine distinct DNAJ cofactors. Of these, DnaJB11 relocalizes to virus-induced replication complexes to promote RNA synthesis, while DnaJB6 associates with capsid protein and facilitates virion biogenesis. Importantly, an allosteric Hsp70 inhibitor, JG40, potently blocks infection of different dengue serotypes in human primary blood cells without eliciting viral resistance or exerting toxicity to the host cells. JG40 also blocks replication of other medically-important flaviviruses including yellow fever, West Nile and Japanese encephalitis viruses. Thus, targeting host Hsp70 subnetworks provides a path for broad-spectrum antivirals.

http://www.sciencedirect.com/sci ... i/S0092867415014026