Hepatitis C virus RNA functionally sequesters miR-122

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

doi:10.1016/j.cell.2015.02.025

Hepatitis C virus RNA functionally sequesters miR-122

Cell. 2015 Mar 12;160(6):1099-110. doi: 10.1016/j.cell.2015.02.025.

Authors

Affiliations

¹ Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA; Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
² Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA; Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Disease and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, and Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
³ Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA; Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA.
⁵ Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
⁶ Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA; Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY 10065, USA.
⁷ Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA; Center for the Study of Hepatitis C, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY 10065, USA.
⁸ Center for the Study of Hepatitis C, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY 10065, USA.
⁹ Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA. Electronic address: ricec@rockefeller.edu.
¹⁰ Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA; New York Genome Center, 101 Avenue of the Americas, New York, NY 10013, USA. Electronic address: darnelr@rockefeller.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Argonaute Proteins / metabolism
Base Sequence
Cell Line, Tumor
Eukaryotic Initiation Factors / metabolism
Hepacivirus / genetics
Hepacivirus / metabolism*
Hepatitis C / metabolism*
Hepatitis C / virology*
Humans
Liver / metabolism
Liver / virology
MicroRNAs / metabolism*
Molecular Sequence Data
RNA, Viral / chemistry
RNA, Viral / metabolism*
Virus Replication

Substances

AGO1 protein, human
Argonaute Proteins
Eukaryotic Initiation Factors
MIRN122 microRNA, human
MicroRNAs
RNA, Viral

Associated data

GEO/GSE64680

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding