A phosphomimetic-based mechanism of dengue virus to antagonize innate immunity

Ying Kai Chan & Michaela U Gack

14-3-3 proteins regulate biological processes by binding to phosphorylated serine or phosphorylated threonine motifs of cellular proteins. Among the 14-3-3 proteins, 14-3-3ε serves a crucial function in antiviral immunity by mediating the cytosol–to–mitochondrial membrane translocation of the pathogen sensor RIG-I. Here we found that the NS3 protein of dengue virus (DV) bound to 14-3-3ε and prevented translocation of RIG-I to the adaptor MAVS and thereby blocked antiviral signaling. Intriguingly, a highly conserved phosphomimetic RxEP motif in NS3 was essential for the binding of 14-3-3ε. A recombinant mutant DV deficient in binding to 14-3-3ε showed impairment in antagonism of RIG-I and elicited 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 might guide the rational design of therapeutics.

http://www.nature.com/ni/journal ... /ni.3393.html#ref17