HCV-induced miR-21 contributes to evasion of host immune system by targeting MyD88 and IRAK1.
HCV-induced miR-21 contributes to evasion of host immune system by targeting MyD88 and IRAK1.
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HCV 诱导的 miR-21 通过靶向 MyD88 和 IRAK1 有助于逃避宿主免疫系统
DOI：
10.1371/journal.ppat.1003248
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Chen Y;Chen J;Wang H;Shi J;Wu K;Liu S;Liu Y;Wu J
在通过模式识别受体（例如Toll样受体（TLR）和视黄酸诱导基因I（RIG-I）样解旋酶）识别病毒组分后，细胞被激活以产生I型干扰素（IFN）和促炎细胞因子。这些途径受到宿主的严格调节，以防止不适当的细胞反应，但病毒可以调节这些途径以增殖和传播。在这项研究中，我们揭示了一种新的机制，其中丙型肝炎病毒（HCV）通过激活microRNA-21（miR-21）逃避免疫监视系统进行增殖。我们证明，HCV感染上调miR-21，进而抑制HCV触发的I型IFN的产生，从而促进HCV复制。此外，我们证明了miR-21靶向TLR信号通路中的两个重要因子，髓样分化因子88（MyD 88）和白细胞介素-1受体相关激酶1（IRAK 1），它们参与HCV诱导的I型IFN产生。HCV介导的miR-21表达的激活需要病毒蛋白和几种信号传导组分。此外，我们鉴定了一种转录因子，激活蛋白-1（AP-1），其部分负责通过PKCε/JNK/c-Jun和PKCα/ERK/c-Fos级联反应诱导miR-21应答HCV感染。综上所述，我们的研究结果表明，miR-21在HCV感染期间上调，并通过MyD 88和IRAK 1负调控IFN-α信号传导，可能是抗病毒干预的潜在治疗靶点。丙型肝炎病毒（HCV）是慢性肝炎、终末期肝硬化和肝细胞癌的主要原因，全世界有2亿人慢性感染，每年有3-4百万人感染。当被病毒感染触发时，宿主细胞产生I型干扰素（IFN）和促炎细胞因子以拮抗病毒。尽管进行了广泛的研究，但HCV免疫系统逃避的机制仍然难以捉摸。我们的研究结果提供了第一个直接证据，即当细胞受到HCV攻击时，microRNA-21（miR-21）反馈抑制I型IFN信号传导，从而促进感染。MicroRNA是一类内源性非编码小RNA，通过与靶mRNA互补配对，调节靶mRNA的表达或翻译，参与先天性和获得性免疫应答，调节多种生物学过程。目前，miRNAs作为疾病的有效靶点或治疗剂引起了许多科学家的兴趣。本研究还发现了HCV诱导I型IFN产生的重要靶点miR-21、髓样分化因子88（MyD 88）和白细胞介素-1受体相关激酶1（IRAK 1），并鉴定了一个转录因子AP-1，该因子参与HCV诱导miR-21产生。总之，我们的研究为理解miRNA对宿主-病毒相互作用的影响提供了新的见解，并揭示了抗病毒干预的潜在治疗靶点。
Upon recognition of viral components by pattern recognition receptors, such as the toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like helicases, cells are activated to produce type I interferon (IFN) and proinflammatory cytokines. These pathways are tightly regulated by the host to prevent an inappropriate cellular response, but viruses can modulate these pathways to proliferate and spread. In this study, we revealed a novel mechanism in which hepatitis C virus (HCV) evades the immune surveillance system to proliferate by activating microRNA-21 (miR-21). We demonstrated that HCV infection upregulates miR-21, which in turn suppresses HCV-triggered type I IFN production, thus promoting HCV replication. Furthermore, we demonstrated that miR-21 targets two important factors in the TLR signaling pathway, myeloid differentiation factor 88 (MyD88) and interleukin-1 receptor-associated kinase 1 (IRAK1), which are involved in HCV-induced type I IFN production. HCV-mediated activation of miR-21 expression requires viral proteins and several signaling components. Moreover, we identified a transcription factor, activating protein-1 (AP-1), which is partly responsible for miR-21 induction in response to HCV infection through PKCε/JNK/c-Jun and PKCα/ERK/c-Fos cascades. Taken together, our results indicate that miR-21 is upregulated during HCV infection and negatively regulates IFN-α signaling through MyD88 and IRAK1 and may be a potential therapeutic target for antiviral intervention. Hepatitis C virus (HCV), a major cause of chronic hepatitis, end-stage cirrhosis, and hepatocellular carcinoma, has chronically infected 200 million people worldwide and 3–4 million more each year. When triggered by viral infection, host cells produce type I interferon (IFN) and proinflammatory cytokines to antagonize the virus. Despite extensive research, the mechanism underlying HCV immune system evasion remains elusive. Our results provided the first direct evidence that microRNA-21 (miR-21) feedback inhibits type I IFN signaling when cells are challenged with HCV, thus promoting the infection. MicroRNA is a kind of endogenous non-coding small RNA that regulates a wide range of biological processes and participate in innate and adaptive immune responses through complementarily pairing with target mRNA, which can regulate its expression or translation. Currently, miRNAs have intrigued many scientists as potent targets or therapeutic agents for diseases. In our study, the targets of miR-21, myeloid differentiation factor 88 (MyD88) and interleukin-1 receptor-associated kinase 1 (IRAK1), which are important for HCV-induced type I IFN production, have also been found. Moreover, we identified a transcription factor, AP-1, which is partly responsible for miR-21 induction in response to HCV infection. Taken together, our research has provided new insights into understanding the effects of miRNA on host-virus interactions, and revealed a potential therapeutic target for antiviral intervention.
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影响因子：
30.8
作者：
Dupuis, S;Jouanguy, E;Casanova, JL
通讯作者：
Casanova, JL
影响因子：
64.5
作者：
HUANG, J;SCHNEIDER, RJ
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作者：
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DOI：
10.1073/pnas.0408707102
发表时间：
2005-02-22
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
5.4
作者：
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