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

Geon Woo Kim, Seung Hoon Lee, Hee Cho, Minwoo Kim, Eui Cheol Shin, Jong Won Oh

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere1005714
JournalPLoS Pathogens
Volume12
Issue number7
DOIs
Publication statusPublished - 2016 Jul

Fingerprint

Hepacivirus
Nucleotides
Liver
Ribonucleotides
MicroRNAs
Down-Regulation
Polynucleotide Adenylyltransferase
High-Throughput Nucleotide Sequencing
Viral RNA
Virus Diseases
Transferases
Life Cycle Stages
Tail
Cytoplasm
Hepatitis C virus nucleocapsid protein
Biopsy

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Kim, Geon Woo ; Lee, Seung Hoon ; Cho, Hee ; Kim, Minwoo ; Shin, Eui Cheol ; Oh, Jong Won. / Hepatitis C Virus Core Protein Promotes miR-122 Destabilization by Inhibiting GLD-2. In: PLoS Pathogens. 2016 ; Vol. 12, No. 7.
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Hepatitis C Virus Core Protein Promotes miR-122 Destabilization by Inhibiting GLD-2. / Kim, Geon Woo; Lee, Seung Hoon; Cho, Hee; Kim, Minwoo; Shin, Eui Cheol; Oh, Jong Won.

In: PLoS Pathogens, Vol. 12, No. 7, e1005714, 07.2016.

Research output: Contribution to journalArticle

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