The Favorable IFNL3 Genotype Escapes MRNA Decay Mediated by AU-rich Elements and Hepatitis C Virus-induced MicroRNAs

Overview

Journal Nat Immunol

Date 2013 Nov 19

PMID 24241692

Citations 87

Authors

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 Jr

Ram Savan

Affiliations

Soon will be listed here.

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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