Zika Virus NS3 Mimics a Cellular 14-3-3-Binding Motif to Antagonize Innate Im...

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Cell Host & Microbe

Zika Virus NS3 Mimics a Cellular 14-3-3-Binding Motif to Antagonize RIG-I- and MDA5-Mediated Innate Immunity

14-3-3 protein family members facilitate the translocation of RIG-I-like receptors to signaling organelles. Riedl et al. show that the NS3 protein of Zika virus physically interacts with the scaffolding proteins 14-3-3ϵ and 14-3-3η to block cytosol-to-mitochondria translocation of the sensors RIG-I and MDA5 and thereby evade antiviral innate immune responses.


Highlights

• •The NS3 protein of Zika virus encodes a highly conserved 14-3-3-binding motif
  
• •NS3 interacts with 14-3-3ϵ and η to inhibit RIG-I and MDA5 signaling, respectively
  
• •NS3 blocks 14-3-3-mediated translocation of RLRs from the cytosol to mitochondria
  
• •A mutant virus deficient in 14-3-3 binding is attenuated due to elevated immunity
  
  

Summary14-3-3 protein family members facilitate the translocation of RIG-I-like receptors (RLRs) to organelles that mediate downstream RLR signaling, leading to interferon production. 14-3-3ϵ promotes the cytosolic-to-mitochondrial translocation of RIG-I, while 14-3-3η facilitates MDA5 translocation to mitochondria. We show that the NS3 protein of Zika virus (ZIKV) antagonizes antiviral gene induction by RIG-I and MDA5 by binding to and sequestering the scaffold proteins 14-3-3ϵ and 14-3-3η. 14-3-3-binding is mediated by a negatively charged RLDP motif in NS3 that is conserved in ZIKV strains of African and Asian lineages and is similar to the one found in dengue and West Nile viruses. ZIKV NS3 is sufficient to inhibit the RLR-14-3-3ϵ/η interaction and to suppress antiviral signaling. Mutational perturbation of 14-3-3ϵ/η binding in a recombinant ZIKV leads to enhanced innate immune responses and impaired growth kinetics. Our study provides molecular understanding of immune evasion functions of ZIKV, which may guide vaccine and anti-flaviviral therapy development.

Graphical Abstract