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

AP McFarland, SM Horner, A Jarret, RC Joslyn… - Nature …, 2014 - nature.com
AP McFarland, SM Horner, A Jarret, RC Joslyn, E Bindewald, BA Shapiro, DA Delker
Nature immunology, 2014nature.com
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 …
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.
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