Regulation of hepatitis C virus genome replication by microRNA-122

microRNA-122 (miR-122) is an abundant, liver-specific miRNA that regulates gene expression post-transcriptionally, typically by binding to the 3' untranslated region (UTR) of mRNAs, repressing their translation and mediating their degradation. Hepatitis C virus (HCV) is uniquely dependent on miR-122. Similar to conventional miRNA action, miR-122 recruits Argonaute-2 (AGO2) protein to the 5' UTR of the viral genome. However, in contrast to typical miRNA function, this stabilizes HCV RNA and slows its decay in infected cells. We found that HCV RNA is degraded primarily by the cytoplasmic 5' exonuclease XRN1 and that miR-122 acts to protect the viral RNA from XRN1-mediated 5' exonucleolytic decay. However, HCV replication still requires miR-122 in XRN1-depleted cells, suggesting additional functions. We also showed that miR-122 enhances HCV RNA synthesis by reducing viral genomes engaged in translation while increasing the fraction available for RNA synthesis. In this review, we summarize the recent progress on the regulatory mechanisms of HCV genome replication by miR-122.