HCV-Induced miR-21 Contributes to Evasion of Host Immune System by Targeting MyD88 and IRAK1

PLoS Pathogens

Hui Wang¹  Shi Liu¹  Yanni Chen¹  Jianguo Wu¹  Jingjing Shi¹  Kailang Wu¹  Junbo Chen²  Yingle Liu³ 

[1] State Key Laboratory of Virology, College of Life Sciences, and Chinese-French Liver Disease Research Institute at Zhongnan Hospital, Wuhan University, Wuhan, Hubei, People′s Republic of China;State Key Laboratory of Virology, Wuhan Institution of Virology, Chinese Academy of Sciences, Wuhan, Hubei, People′s Republic of China;Wuhan Institute of Biotechnology, Wuhan East Lake High Technology Development Zone, Wuhan, Hubei, People′s Republic of China

关键词: Hepatocytes;    Small interfering RNAs;    MicroRNAs;    Interferons;    Transcription factors;    Hepatitis C virus;    Luciferase;    Viral replication;   

DOI  :  10.1371/journal.ppat.1003248

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY