Department of Microbiology, The University of Chicago, Chicago, IL 60637, USA.
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
Cell Host Microbe. 2019 Oct 9;26(4):493-503.e6. doi: 10.1016/j.chom.2019.09.012.
14-3-3 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.
14-3-3 蛋白家族成员促进 RIG-I 样受体 (RLRs) 易位到介导下游 RLR 信号的细胞器，导致干扰素的产生。14-3-3ε促进 RIG-I 的细胞质到线粒体易位，而 14-3-3η 则促进 MDA5 易位到线粒体。我们发现 Zika 病毒 (ZIKV) 的 NS3 蛋白通过与支架蛋白 14-3-3ε和 14-3-3η结合并将其隔离，拮抗 RIG-I 和 MDA5 的抗病毒基因诱导。14-3-3 结合由 NS3 中的一个带负电荷的 RLDP 基序介导，该基序在非洲和亚洲谱系的 ZIKV 株中保守，与登革热和西尼罗河病毒中的基序相似。ZIKV NS3 足以抑制 RLR-14-3-3ε/η 相互作用并抑制抗病毒信号。在重组 ZIKV 中对 14-3-3ε/η 结合进行突变干扰会导致先天免疫反应增强和生长动力学受损。我们的研究为 ZIKV 的免疫逃避功能提供了分子理解，这可能为疫苗和抗黄病毒治疗的发展提供指导。
