The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs.

Adelle P McFarland, Stacy M Horner, Abigail Jarret, Rochelle C Joslyn, Eckart Bindewald, Bruce A Shapiro, Don A Delker, Curt H Hagedorn, Mary Carrington, Michael Gale, Ram Savan

Journal: Nature immunology 2014;15(1):72-9

PMID: 24241692

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Abstract

IFNL3, which encodes interferon-λ3 (IFN-λ3), has received considerable attention in the hepatitis C virus (HCV) field, as many independent genome-wide association studies have identified a strong association between polymorphisms near IFNL3 and clearance of HCV. However, the mechanism underlying this association has remained elusive. In this study, we report the identification of a functional polymorphism (rs4803217) in the 3' untranslated region (UTR) of IFNL3 mRNA that dictated transcript stability. We found that this polymorphism influenced AU-rich element (ARE)-mediated decay (AMD) of IFNL3 mRNA, as well as the binding of HCV-induced microRNAs during infection. Together these pathways mediated robust repression of the unfavorable IFNL3 polymorphism. Our data reveal a previously unknown mechanism by which HCV attenuates the antiviral response and indicate new potential therapeutic targets for HCV treatment.

Address: Department of Immunology, University of Washington, Seattle, Washington, USA.; 1] Department of Immunology, University of Washington, Seattle, Washington, USA. [2].; Basic Science Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.; Center for Cancer Research Nanobiology Program, National Cancer Institute, Frederick, Maryland, USA.; Divison of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Utah, Salt Lake City, Utah, USA.; 1] Divison of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Utah, Salt Lake City, Utah, USA. [2].; 1] Cancer and Inflammation Program, Laboratory of Experimental Immunology, Science Applications International Corporation-Frederick, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. [2] Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.

DOI: 10.1038/ni.2758

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MeSH Terms: 3' Untranslated Regions, AU Rich Elements, Base Sequence, Cell Line, Tumor, Flow Cytometry, Genotype, Hep G2 Cells, Hepacivirus, Hepatitis C, Host-Pathogen Interactions, Humans, Interferons, Interleukins, Liver Neoplasms, MicroRNAs, Molecular Sequence Data, Polymorphism, Single Nucleotide, RNA Stability, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Nucleic Acid