title: A phosphomimetic-based mechanism of dengue virus to antagonize innate immunity.
abstract: 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, 14-3-3ɛ 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 14-3-3ɛ 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 14-3-3ɛ. A recombinant mutant DV deficient in binding to 14-3-3ɛ 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.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ying Kai
authors.initials: YK
authors.lastname: Chan
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Microbiology, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Michaela U
authors.initials: MU
authors.lastname: Gack
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000595:Amino Acid Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D015151:Immunoblotting; D018613:Microscopy, Confocal; D010766:Phosphorylation / Q000276:immunology; D034622:RNA Interference / Q000276:immunology; D011971:Receptors, Immunologic; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000085242:Viral Proteases
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D011971:Receptors, Immunologic; D012697:Serine Endopeptidases; C505371:MAVS protein, human; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases; C452820:RIGI protein, human