Hepatitis C Virus RNA Functionally Sequesters MiR-122

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2015 Mar 14

PMID 25768906

Citations 205

Authors

Joseph M Luna

Troels K H Scheel

Tal Danino

Katharina S Shaw

Aldo Mele

John J Fak

Eiko Nishiuchi

Constantin N Takacs

Maria Teresa Catanese

Ype P de Jong

Ira M Jacobson

Charles M Rice

Robert B Darnell

Affiliations

Soon will be listed here.

Abstract

Hepatitis C virus (HCV) uniquely requires the liver-specific microRNA-122 for replication, yet global effects on endogenous miRNA targets during infection are unexplored. Here, high-throughput sequencing and crosslinking immunoprecipitation (HITS-CLIP) experiments of human Argonaute (AGO) during HCV infection showed robust AGO binding on the HCV 5'UTR at known and predicted miR-122 sites. On the human transcriptome, we observed reduced AGO binding and functional mRNA de-repression of miR-122 targets during virus infection. This miR-122 "sponge" effect was relieved and redirected to miR-15 targets by swapping the miRNA tropism of the virus. Single-cell expression data from reporters containing miR-122 sites showed significant de-repression during HCV infection depending on expression level and site number. We describe a quantitative mathematical model of HCV-induced miR-122 sequestration and propose that such miR-122 inhibition by HCV RNA may result in global de-repression of host miR-122 targets, providing an environment fertile for the long-term oncogenic potential of HCV.

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