Portal de Periódicos da CAPES

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

2013; Nature Portfolio; Volume: 15; Issue: 1 Linguagem: Inglês

10.1038/ni.2758

1529-2916

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,

Cancer-related molecular mechanisms research

Polymorphisms near genes encoding members of the IFN-λ family are associated with susceptibility or resistance to hepatitis C virus. Savan and colleagues show that differences in the stability of transcripts of those genes underlie the mechanism of resistance to that virus. 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.