Hepatitis C virus RNA functionally sequesters miR-122

TY - JOUR

T1 - Hepatitis C virus RNA functionally sequesters miR-122

AU - Luna, Joseph M

AU - Scheel, Troels K H

AU - Danino, Tal

AU - Shaw, Katharina S

AU - Mele, Aldo

AU - Fak, John J

AU - Nishiuchi, Eiko

AU - Takacs, Constantin N

AU - Catanese, Maria Teresa

AU - de Jong, Ype P

AU - Jacobson, Ira M

AU - Rice, Charles M

AU - Darnell, Robert B

N1 - Copyright © 2015 Elsevier Inc. All rights reserved.

PY - 2015/3/15

Y1 - 2015/3/15

N2 - 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.

AB - 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.

KW - Argonaute Proteins

KW - Base Sequence

KW - Cell Line, Tumor

KW - Eukaryotic Initiation Factors

KW - Hepacivirus

KW - Hepatitis C

KW - Humans

KW - Liver

KW - MicroRNAs

KW - Molecular Sequence Data

KW - RNA, Viral

KW - Virus Replication

U2 - 10.1016/j.cell.2015.02.025

DO - 10.1016/j.cell.2015.02.025

M3 - Journal article

C2 - 25768906

SN - 0092-8674

VL - 160

SP - 1099

EP - 1110

JO - Cell

JF - Cell

IS - 6

ER -