Hepatitis C Virus Core Protein Promotes miR-122 Destabilization by Inhibiting GLD-2

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′ end by 3′-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′-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′ 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. © 2016 kim et al.