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Mosquito-transmitted flaviviruses, including the recently emergent Zika virus (ZIKV), represent a major human health concern. Detection of viral infection by cellular pattern recognition receptors (PRRs) is a critical first step in generating a type-I interferon (IFN) mediated antiviral program. RIG-I and MDA5, the PRRs responsible for detecting cytosolic RNA, bind to viral nucleic acid and initiate downstream signaling by interacting with the downstream adaptor protein MAVS. Translocation of these sensors from the cytosolic site of RNA detection to the mitochondria is mediated by binding to cellular 14-3-3 chaperone proteins. ZIKV NS3 encodes a phosphomimetic 14-3-3-binding motif (64-RLDP-67) that mediates an interaction between NS3 and 14-3-3 proteins. In the context of viral infection, mutational perturbation of the 14-3-3 interaction site in NS3 spurs an enhanced production of cytokines and impairs ZIKV infection. Our results demonstrate that ZIKV NS3 evades RIGI- and MDA5-mediated innate immunity through an NS3-14-3-3 protein interaction, and loss of this evasion ability attenuates viral replication. Furthermore, an ability to bind to 14-3-3 proteins is conserved in other members of Flaviviridae.



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