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

PLoS Pathogens

Seung-Hoon Lee¹  Geon-Woo Kim¹  Minwoo Kim¹  Jong-Won Oh¹  Hee Cho¹  Eui-Cheol Shin² 

[1] Department of Biotechnology, Yonsei University, Seoul, Korea;Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea

关键词: MicroRNAs;    Isomers;    Biopsy;    Hepatitis C virus;    Viral core;    RNA sequencing;    Protein expression;    Small interfering RNAs;   

DOI  :  10.1371/journal.ppat.1005714

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY