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

Abstract

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.