The TRK-fused gene negatively regulates interferon signaling by inhibiting TBK1 phosphorylation during PPMV-1 infection

文献类型： 外文期刊

第一作者： Tian, Ye

作者： Tian, Ye;Liu, Liping;Lv, Junfeng;Xue, Ruixue;Chen, Shumin;Yu, Cuilian;Yu, Cuilian

作者机构：

关键词： TFG; IFN response; phosphorylation; TBK1; PPMV-1

期刊名称：ACTA VIROLOGICA （ 影响因子：1.7； 五年影响因子：1.4 ）

ISSN： 0001-723X

年卷期： 2023 年 67 卷

页码：

收录情况： SCI

摘要： TRK-fused gene (TFG, tropomyosin-receptor kinase fused gene) is known to negatively regulate the retinoic acid inducible gene (RIG)-I-like receptor (RLR)-mediated interferon (IFN)-I pathway in human cells, thereby participating in the paramyxovirus infection process. We showed that pigeon paramyxovirus type 1 (PPMV-1) infection significantly upregulates TFG expression in infected cells at an early stage. We speculated that PPMV-1 would inhibit IFN activation by upregulating a negative regulator of the IFN pathway. This hypothesis was proved when TFG protein expression was knocked down by RNAi and the replication level of PPMV-1 virus decreased, which indicated that TFG upregulation in the early infection stage benefit virus replication. We next used the IFN-beta promoter reporter system to evaluate the role of the TFG in the IFN pathway. The results showed that the TFG inhibited the IFN-beta expression stimulated by RIG-I, MAVS (mitochondrial antiviral signaling protein) and TANK-binding kinase 1 (TBK1), but did not inhibit IFN-beta activated by the interferon regulatory transcription factor 3 (IRF3), indicating that TFG may affect the function of TBK1, which play an important role in phosphorylation of the IRF3. Further experiments showed that the TFG inhibited the phosphorylation of TBK1, resulting in IRF3 being unable to be phosphorylated. Subsequent experiments on IFN pathway activation confirmed that the IRF3 phosphorylation level was significantly downregulated after overexpression of TFG, while the IFN-beta promoter reporting experiment showed that TFG did not directly inhibit the IFN response activated by IRF3. This confirmed that TFG protein negatively regulates the IFN-beta pathway by inhibiting TBK1 phosphorylation.

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