Foot-and-mouth disease virus induces lysosomal degradation of NME1 to impair p53-regulated interferon-inducible antiviral genes expression

文献类型： 外文期刊

第一作者： Feng, Huan-Huan

作者： Feng, Huan-Huan;Zhu, Zi-Xiang;Cao, Wei-Jun;Yang, Fan;Zhang, Xiang-Le;Du, Xiao-Li;Zhang, Ke-Shan;Liu, Xiang-Tao;Zheng, Hai-Xue

作者机构：

期刊名称：CELL DEATH & DISEASE （ 影响因子：8.469； 五年影响因子：8.713 ）

ISSN： 2041-4889

年卷期： 2018 年 9 卷

页码：

收录情况： SCI

摘要： Nucleoside diphosphate kinase 1 (NME1) is well-known as a tumor suppressor that regulates p53 function to prevent cancer metastasis and progression. However, the role of NME1 in virus-infected cells remains unknown. Here, we showed that NME1 suppresses viral replication in foot-and-mouth disease virus (FMDV)-infected cells. NME1-enhanced p53-mediated transcriptional activity and induction of interferon-inducible antiviral genes expression. FMDV infection decreased NME1 protein expression. The 2B and VP4 proteins were identified as the viral factors that induced reduction of NME1. FMDV 2B protein has a suppressive effect on host protein expression. We measured, for the first time, VP4-induced lysosomal degradation of host protein; VP4-induced degradation of NME1 through the macroautophagy pathway, and impaired p53-mediated signaling. p53 plays significant roles in antiviral innate immunity by inducing several interferon-inducible antiviral genes expression, such as, ISG20, IRF9, RIG-I, and ISG15. VP4 promoted interaction of p53 with murine double minute 2 (MDM2) through downregulation of NME1 resulting in destabilization of p53. Therefore, 5-flurouracil-induced upregulation of ISG20, IRF9, RIG-I, and ISG15 were suppressed by VP4. VP4-induced reduction of NME1 was not related to the well-characterized blocking effect of FMDV on cellular translation, and no direct interaction was detected between NME1 and VP4. The 15-30 and 75-85 regions of VP4 were determined to be crucial for VP4-induced reduction of NME1. Deletion of these VP4 regions also inhibited the suppressive effect of VP4 on NME1-enhanced p53 signaling. In conclusion, these data suggest an antiviral role of NME1 by regulation of p53-mediated antiviral innate immunity in virus-infected cells, and reveal an antagonistic mechanism of FMDV that is mediated by VP4 to block host innate immune antiviral response.

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