Chan, Ying KaiGack, Michaela U.2016-11-182016Chan, Ying Kai, and Michaela U. Gack. 2016. “A phosphomimetic-based mechanism of dengue virus to antagonize innate immunity.” Nature immunology 17 (5): 523-530. doi:10.1038/ni.3393. http://dx.doi.org/10.1038/ni.3393.1529-2908http://nrs.harvard.edu/urn-3:HUL.InstRepos:2940758714-3-3 proteins regulate biological processes by binding to phospho-Ser or phospho-Thr motifs of cellular proteins. Among them, 14-3-3ε is crucial for antiviral immunity by mediating the cytosol-to-mitochondrial-membrane translocation of the pathogen sensor RIG-I. Here we show that the NS3 protein of dengue virus (DV) binds to 14-3-3ε and prevents RIG-I translocation to the adaptor MAVS, thereby blocking antiviral signaling. Intriguingly, a highly conserved phosphomimetic RxEP motif in NS3 is essential for 14-3-3ε binding. A recombinant mutant DV deficient in 14-3-3ε binding is impaired in RIG-I antagonism and elicits a markedly augmented innate immune response and enhanced T cell activation. Our work reveals a novel phosphomimetic-based mechanism for viral antagonism of 14-3-3-mediated immunity, which may guide the rational design of therapeutics.en-USJournal Article2016-11-1810.1038/ni.3393