Defining Hsp70 subnetworks in dengue virus replication reveals key vulnerability in flavivirus infection

Shuhei Taguwa, Kevin Maringer, Xiaokai Li, Dabeiba Bernal-Rubio, Jennifer N. Rauch, Jason E. Gestwicki, Raul Andino, Ana Fernandez-Sesma, Judith Frydman

Cell, 2015. 163, 1108-1123

Speaker: Wan-Yu Wang (王琬瑜)                                         Time: 15:00~16:00, May 25, 2016

Commentator: Dr. Chai-Yi Yu (余佳益老師)                       Place: Room 601

Abstract:

Dengue is the most common arboviral infection globally with about 390 million infections annually. Dengue virus (DENV) is a positive single-stranded RNA virus, and belongs to Flaviviridae family, Flavivirus genus with four serotypes. All of the four serotypes cause a range of diseases including dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). So far, no specific antiviral drugs are licensed for human ^[1]. The host chaperones are reported to stabilize viral proteins and facilitate flavivirus replication ^{[2, 3]}. However, the interplay between chaperone networks and DENV life cycle remains unclear. Deficiency of cytosolic Hsp70 down-regulated multiple steps of the viral cycle including entry, RNA replication, and virus production. In addition, Hsp70 is required to the folding of DENV polymerase NS5. Moreover, it associates with DENV capsid protein and participates in virion production. The Hsp70 inhibitor, JG40, blocked DENV infection with low risk of drug resistance and without cytotoxicity. The authors selected different Hsp70 cofactors (DNAJ isoforms) which localized in distinct cellular compartments leading to productive DENV infection. The DnaJB11 localized in viral replication complexes to promoted RNA synthesis, while DnaJB6 associated with capsid protein and promote the production of DENV. JG40 also inhibited the replication of divergent Flaviviruses and modulated a subset of cytokines production in DENV-infected human monocyte-derived dendritic cells (MDDCs). In conclusion, the study provides a path for broad-spectrum antivirals by targeting host Hsp70 subnetworks.

References:

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3.         Nagy, P.D., et al. The dependence of viral RNA replication on co-opted host factors. Nat. Rev. Microbiol. 2012. 10, 137–149.