IFNL3 (IL28B) favorable genotype escapes hepatitis C virus-induced microRNAs and mRNA decay

The IFNL3 (IL28B) gene has received immense attention in the hepatitis C virus (HCV) field as multiple independent genome-wide association studies identified a strong association between polymorphisms near the IFNL3 gene and HCV clearance. However, the mechanism underlying this association has remai...

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Autores principales: McFarland, Adelle P., Horner, Stacy M., Jarret, Abigail, Joslyn, Rochelle C., Bindewald, Eckart, Shapiro, Bruce A., Delker, Don A., Hagedorn, Curt, Carrington, Mary, Gale, Michael, Savan, Ram
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183367/
https://www.ncbi.nlm.nih.gov/pubmed/24241692
http://dx.doi.org/10.1038/ni.2758
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author McFarland, Adelle P.
Horner, Stacy M.
Jarret, Abigail
Joslyn, Rochelle C.
Bindewald, Eckart
Shapiro, Bruce A.
Delker, Don A.
Hagedorn, Curt
Carrington, Mary
Gale, Michael
Savan, Ram
author_facet McFarland, Adelle P.
Horner, Stacy M.
Jarret, Abigail
Joslyn, Rochelle C.
Bindewald, Eckart
Shapiro, Bruce A.
Delker, Don A.
Hagedorn, Curt
Carrington, Mary
Gale, Michael
Savan, Ram
author_sort McFarland, Adelle P.
collection PubMed
description The IFNL3 (IL28B) gene has received immense attention in the hepatitis C virus (HCV) field as multiple independent genome-wide association studies identified a strong association between polymorphisms near the IFNL3 gene and HCV clearance. However, the mechanism underlying this association has remained elusive. In this study, we report the identification of a functional polymorphism (rs4803217) located in the 3′ untranslated region (3′ UTR) of the IFNL3 mRNA that dictates transcript stability. This polymorphism influences AU-rich element-mediated decay as well as the binding of HCV-induced microRNAs during infection. Together, these pathways mediate robust repression of the unfavorable IFNL3 genotype. These data reveal a novel mechanism by which HCV attenuates the antiviral response and uncover new potential therapeutic targets for HCV treatment.
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spelling pubmed-41833672014-10-02 IFNL3 (IL28B) favorable genotype escapes hepatitis C virus-induced microRNAs and mRNA decay McFarland, Adelle P. Horner, Stacy M. Jarret, Abigail Joslyn, Rochelle C. Bindewald, Eckart Shapiro, Bruce A. Delker, Don A. Hagedorn, Curt Carrington, Mary Gale, Michael Savan, Ram Nat Immunol Article The IFNL3 (IL28B) gene has received immense attention in the hepatitis C virus (HCV) field as multiple independent genome-wide association studies identified a strong association between polymorphisms near the IFNL3 gene and HCV clearance. However, the mechanism underlying this association has remained elusive. In this study, we report the identification of a functional polymorphism (rs4803217) located in the 3′ untranslated region (3′ UTR) of the IFNL3 mRNA that dictates transcript stability. This polymorphism influences AU-rich element-mediated decay as well as the binding of HCV-induced microRNAs during infection. Together, these pathways mediate robust repression of the unfavorable IFNL3 genotype. These data reveal a novel mechanism by which HCV attenuates the antiviral response and uncover new potential therapeutic targets for HCV treatment. 2013-11-17 2014-01 /pmc/articles/PMC4183367/ /pubmed/24241692 http://dx.doi.org/10.1038/ni.2758 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
McFarland, Adelle P.
Horner, Stacy M.
Jarret, Abigail
Joslyn, Rochelle C.
Bindewald, Eckart
Shapiro, Bruce A.
Delker, Don A.
Hagedorn, Curt
Carrington, Mary
Gale, Michael
Savan, Ram
IFNL3 (IL28B) favorable genotype escapes hepatitis C virus-induced microRNAs and mRNA decay
title IFNL3 (IL28B) favorable genotype escapes hepatitis C virus-induced microRNAs and mRNA decay
title_full IFNL3 (IL28B) favorable genotype escapes hepatitis C virus-induced microRNAs and mRNA decay
title_fullStr IFNL3 (IL28B) favorable genotype escapes hepatitis C virus-induced microRNAs and mRNA decay
title_full_unstemmed IFNL3 (IL28B) favorable genotype escapes hepatitis C virus-induced microRNAs and mRNA decay
title_short IFNL3 (IL28B) favorable genotype escapes hepatitis C virus-induced microRNAs and mRNA decay
title_sort ifnl3 (il28b) favorable genotype escapes hepatitis c virus-induced micrornas and mrna decay
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183367/
https://www.ncbi.nlm.nih.gov/pubmed/24241692
http://dx.doi.org/10.1038/ni.2758
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