title: Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection.
abstract: 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.
authors.affiliation: Department of Biology and Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Taguwa
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Maringer
authors.affiliation: Department of Pharmaceutical Chemistry University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Xiaokai
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Dabeiba
authors.initials: D
authors.lastname: Bernal-Rubio
authors.affiliation: Department of Pharmaceutical Chemistry University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Rauch
authors.affiliation: Department of Pharmaceutical Chemistry University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.affiliation: Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Andino
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Sesma
authors.affiliation: Department of Biology and Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address: jfrydman@stanford.edu.
authors.forename: Judith
authors.initials: J
authors.lastname: Frydman
mesh_terms: D000818:Animals; D036022:Capsid Proteins / Q000378:metabolism; D009033:Culicidae / Q000821:virology; D003715:Dengue / Q000378:metabolism / Q000821:virology*; D003716:Dengue Virus; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D014779:Virus Replication / Q000187:drug effects
chemical_list: D036022:Capsid Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins