A phosphomimetic-based mechanism of dengue virus to antagonize innate immunity.
A phosphomimetic-based mechanism of dengue virus to antagonize innate immunity.
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DOI：
10.1038/ni.3393
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发表时间：
2016-05
影响因子：
30.5
通讯作者：
Gack MU
中科院分区：
文献类型：
--
作者：
Chan YK;Gack MU
14-3-3蛋白通过与细胞蛋白的磷酸-Ser或磷酸-Thr基序结合来调节生物过程。其中，14-3-3ε通过介导病原体传感器RIG-I的胞质到胞膜的易位而对抗病毒免疫至关重要。在这里，我们表明登革病毒（DV）的NS 3蛋白结合14-3-3ε，并阻止RIG-I易位到接头MAVS，从而阻断抗病毒信号。有趣的是，NS 3中高度保守的磷酸化模拟RxEP基序对于14-3-3ε结合是必需的。14-3-3ε结合缺陷的重组突变体DV在RIG-I拮抗作用中受损，并显著增强先天免疫应答和增强T细胞活化。我们的工作揭示了一种新的基于拟磷酸化的机制，用于病毒拮抗14-3-3介导的免疫，这可能会指导合理的治疗设计。
14-3-3 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.