School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
The Institute of Cancer Molecular Mechanisms and Drug Targets, School of Basic Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, China.
FASEB J. 2019 Sep;33(9):9929-9944. doi: 10.1096/fj.201900260R. Epub 2019 Jun 10.
Recently, Zika virus (ZIKV) has generated extraordinary concern because of its severe neurotoxicity. Disturbingly, there is no vaccine or specific drug to prevent or treat the diseases caused by ZIKV infection. Thus, it is extremely urgent to characterize the pathogenesis of ZIKV. It has been documented that ZIKV can evade antiviral responses of host cells. Here, we demonstrate that ZIKV strain SZ-WIV01 down-regulates the production of type I IFN and IFN-stimulated genes along with the expression of mitochondrial antiviral signaling protein (MAVS) and mediator of IFN regulatory factor 3 activation (MITA). In the mechanism, ZIKV nonstructural (NS) 3 and NS2B3 negatively regulate IFN-related retinoic acid-inducible gene I-like receptor signaling pathway by targeting MAVS and MITA, respectively. Overexpression of ZIKV NS3 and NS2B3 dramatically inhibits expression of IFN-β. ZIKV NS3 interacts with MAVS, and NS2B3 interacts with MITA, which catalyzes K48-linked polyubiquitination of MAVS and MITA for degradation. Further investigations suggest that ZIKV NS2B3 impairs polyinosinic:polycytidylic acid-triggered K63-linked polyubiquitination of MITA, thereby subverting the activation of downstream sensors. Our study reveals an undiscovered mechanism for ZIKV to escape the innate immune response, providing new insights into clinical study of vaccines or effective drugs.-Li, W., Li, N., Dai, S., Hou, G., Guo, K., Chen, X., Yi, C., Liu, W., Deng, F., Wu, Y., Cao, X. Zika virus circumvents host innate immunity by targeting the adaptor proteins MAVS and MITA.
最近，寨卡病毒（ZIKV）因其严重的神经毒性而引起了极大的关注。令人不安的是，目前还没有疫苗或特定药物来预防或治疗 ZIKV 感染引起的疾病。因此，描述 ZIKV 的发病机制迫在眉睫。已有文献证明，ZIKV 可以逃避宿主细胞的抗病毒反应。在这里，我们证明 ZIKV 株 SZ-WIV01 下调了 I 型 IFN 的产生以及 IFN 刺激基因的表达，同时下调了线粒体抗病毒信号蛋白（MAVS）和 IFN 调节因子 3 激活介质（MITA）的表达。在机制上，ZIKV 的非结构（NS）3 和 NS2B3 通过分别靶向 MAVS 和 MITA，负调控 IFN 相关的视黄酸诱导基因 I 样受体信号通路。ZIKV NS3 和 NS2B3 的过表达显著抑制 IFN-β的表达。ZIKV NS3 与 MAVS 相互作用，NS2B3 与 MITA 相互作用，催化 MAVS 和 MITA 的 K48 连接多泛素化降解。进一步的研究表明，ZIKV NS2B3 破坏了多聚肌苷酸：多聚胞苷酸触发的 MITA 的 K63 连接多泛素化，从而颠覆了下游传感器的激活。我们的研究揭示了 ZIKV 逃避先天免疫反应的一个未被发现的机制，为疫苗或有效药物的临床研究提供了新的见解。-李，W.，李，N.，戴，S.，侯，G.，郭，K.，陈，X.，易，C.，刘，W.，邓，F.，吴，Y.，曹，X. 寨卡病毒通过靶向衔接蛋白 MAVS 和 MITA 来规避宿主先天免疫。
