Paragraph: The liver-specific microRNA miR-122, which has essential roles in liver development and metabolism, is a key proviral factor for hepatitis C virus (HCV). Despite its crucial role in the liver and HCV life cycle, little is known about the molecular mechanism of miR-122 expression regulation by HCV infection. Here, we show that the HCV core protein downregulates the abundance of miR-122 by promoting its destabilization via the inhibition of GLD-2, a non-canonical cytoplasmic poly(A) polymerase. The decrease in miR-122 expression resulted in the dysregulation of the known functions of miR-122, including its proviral activity for HCV. By high-throughput sequencing of small RNAs from human liver biopsies, we found that the 22-nucleotide (nt) prototype miR-122 is modified at its 3 0 end by 3 0 -terminal non-templated and templated nucleotide additions. Remarkably, the proportion of miR-122 isomers bearing a single nucleotide tail of any ribonucleotide decreased in liver specimens from patients with HCV. We found that these single-nucleotide-tailed miR-122 isomers display increased miRNA activity and stability over the 22-nt prototype miR-122 and that the 3 0 -terminal extension is catalyzed by the unique terminal nucleotidyl transferase activity of GLD-2, which is capable of adding any single ribonucleotide without preference of adenylate to the miR-122 3 0 end. The HCV core protein specifically inhibited GLD-2, and its interaction with GLD-2 in the cytoplasm was found to be responsible for miR-122 downregulation. Collectively, our results provide new insights into the regulatory role of the HCV core protein in controlling viral RNA abundance and miR-122 functions through miR-122 stability modulation. Viruses may benefit from altering the host cell's normal miRNA milieu, by either lowering or increasing antiviral or proviral miRNA levels. Our results reveal a mechanism by which virus infection can regulate miRNA abundance by modulating the activity of cellular enzymes responsible for miRNA 3 0 -terminal modifications. Hepatitis C virus (HCV) uses microRNA-122 (miR-122) as a proviral host factor to increase viral genome abundance, but HCV infection results in diminished miR-122 levels by unknown mechanisms. We PLOS Pathogens | demonstrated that the HCV core protein plays a role in reprogramming the cellular profile of miR-122 isomers by inhibiting GLD-2, a non-canonical cytoplasmic poly(A) polymerase, to promote miR-122 destabilization. Our results raise several important questions. First, how is only a specific subset of miRNAs in the liver affected by GLD-2 inhibition by the HCV core protein? Second, how does HCV regulate pre-miR-122 processing in its loop region? Third, does GLD-2 inhibition by the HCV core protein affect the translation of a specific group of host mRNAs? With many unanswered questions, our results propose a novel feedback regulatory mechanism for controlling HCV RNA abundance by the viral capsid protein, which is capable of modulating miR-122 activity and stability through the inhibition of GLD-2. GLD-2 Inhibition by the HCV Core Protein PLOS Pathogens | 
 Title: Hepatitis C Virus Core Protein Promotes miR- 122 Destabilization by Inhibiting GLD-2
Output: False