Transforming growth factor β-activated kinase 1 transcriptionally suppresses hepatitis B virus replication.
Transforming growth factor β-activated kinase 1 transcriptionally suppresses hepatitis B virus replication.
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DOI：
10.1038/srep39901
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发表时间：
2017-01-03
影响因子：
4.6
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Pang J;Zhang G;Lin Y;Xie Z;Liu H;Tang L;Lu M;Yan R;Guo H;Sun J;Hou J;Zhang X
B型肝炎病毒（HBV）在肝细胞中的复制受到宿主先天免疫系统和相关细胞内信号传导途径的限制。转化生长因子β激活激酶1（Transforming growth factor β-activated kinase 1，TAK 1）是Toll样受体和促炎细胞因子信号通路的关键介质。在这里，我们报告说，沉默或抑制肝癌细胞系内源性TAK 1导致HBV复制，转录和抗原表达上调。相反，TAK 1的过表达显著抑制HBV复制，而TAK 1的酶失活形式不发挥作用。通过筛选TAK 1相关信号通路的抑制剂和siRNA，我们发现MAPK-JNK通路参与TAK 1介导的HBV抑制。此外，TAK 1敲低或JNK途径抑制诱导法尼醇X受体α的表达，法尼醇X受体α是上调HBV转录的转录因子。最后，TAK 1在HBV流体动力学注射小鼠模型中的异位表达导致肝脏和血清中HBV DNA和抗原水平降低。总之，我们的数据表明TAK 1主要通过激活MAPK-JNK途径在病毒转录水平抑制HBV，因此TAK 1代表了HBV在肝细胞中复制的内在宿主限制因子。
Hepatitis B Virus (HBV) replication in hepatocytes is restricted by the host innate immune system and related intracellular signaling pathways. Transforming growth factor β-activated kinase 1 (TAK1) is a key mediator of toll-like receptors and pro-inflammatory cytokine signaling pathways. Here, we report that silencing or inhibition of endogenous TAK1 in hepatoma cell lines leads to an upregulation of HBV replication, transcription, and antigen expression. In contrast, overexpression of TAK1 significantly suppresses HBV replication, while an enzymatically inactive form of TAK1 exerts no effect. By screening TAK1-associated signaling pathways with inhibitors and siRNAs, we found that the MAPK-JNK pathway was involved in TAK1-mediated HBV suppression. Moreover, TAK1 knockdown or JNK pathway inhibition induced the expression of farnesoid X receptor α, a transcription factor that upregulates HBV transcription. Finally, ectopic expression of TAK1 in a HBV hydrodynamic injection mouse model resulted in lower levels of HBV DNA and antigens in both liver and serum. In conclusion, our data suggest that TAK1 inhibits HBV primarily at viral transcription level through activation of MAPK-JNK pathway, thus TAK1 represents an intrinsic host restriction factor for HBV replication in hepatocytes.
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影响因子：
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DOI：
10.1073/pnas.0401771101
发表时间：
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影响因子：
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作者：
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通讯作者：
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