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

The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs.
Published: 
Jan 2015
Publisher: 
Nat Immunol. 2014 Jan;15(1):72-9. doi: 10.1038/ni.2758. Epub 2013 Nov 17.
Author: 
Ram Savan, Ph.D.

McFarland AP1, Horner SM2, Jarret A1, Joslyn RC1, Bindewald E3, Shapiro BA4, Delker DA5, Hagedorn CH6, Carrington M7, Gale M Jr1, Savan R1.

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.

PMID:24241692
PMCID:PMC4183367