The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs.
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.
Department of Immunology, University of Washington, Seattle, Washington, USA.
Adelle P
AP
McFarland
1] Department of Immunology, University of Washington, Seattle, Washington, USA. [2].
Stacy M
SM
Horner
Department of Immunology, University of Washington, Seattle, Washington, USA.
Abigail
A
Jarret
Department of Immunology, University of Washington, Seattle, Washington, USA.
Rochelle C
RC
Joslyn
Basic Science Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Eckart
E
Bindewald
Center for Cancer Research Nanobiology Program, National Cancer Institute, Frederick, Maryland, USA.
Bruce A
BA
Shapiro
Divison of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Utah, Salt Lake City, Utah, USA.
Don A
DA
Delker
1] Divison of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Utah, Salt Lake City, Utah, USA. [2].
Curt H
CH
Hagedorn
1] Cancer and Inflammation Program, Laboratory of Experimental Immunology, Science Applications International Corporation-Frederick, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. [2] Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.
Mary
M
Carrington
Department of Immunology, University of Washington, Seattle, Washington, USA.
Michael
M
Gale
Department of Immunology, University of Washington, Seattle, Washington, USA.
Ram
R
Savan
D020413:3' Untranslated Regions / Q000235:genetics; D063307:AU Rich Elements / Q000235:genetics*; D001483:Base Sequence; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D005838:Genotype; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000502:physiology; D006526:Hepatitis C / Q000235:genetics / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D020871:RNA Stability / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D000095022:Interferon Lambda
D020413:3' Untranslated Regions; D007372:Interferons; D007378:Interleukins; D035683:MicroRNAs; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C550906:MIRN208 microRNA, human; C548683:MIRN499 microRNA, human