Zhou, Hao; Møhlenberg, Michelle; Terczyńska-Dyla, Ewa; Winther, Kasper Grønbjerg; Hansen, Nanna Hougaard; Vad-Nielsen, Johan; Laloli, Laura; Dijkman, Ronald; Nielsen, Anders Lade; Gad, Hans Henrik; Hartmann, Rune (2020). The IFNL4 gene is a non-canonical interferon gene with a unique but evolutionarily conserved regulation. Journal of virology, 94(5) American Society for Microbiology 10.1128/JVI.01535-19
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Journal of Virology-2019-Zhou-JVI.01535-19.full.pdf - Accepted Version Available under License Publisher holds Copyright. Download (3MB) | Preview |
Interferon lambda 4 (IFNL4) is a recently identified enigmatic member of the interferon lambda family. Genetic data suggest that the IFNL4 gene acts in a pro-viral and anti-inflammatory manner in patients. However, the protein is in vitro indistinguishable from the other members of the interferon lambda family. We have investigated the gene regulation of IFNL4 in detail and found that it differs radically from that of canonical antiviral interferons. Being induced by viral infection is a defining characteristic of interferons, but viral infection or overexpression of members of the interferon regulatory factor (IRF) family of transcription factors only leads to a minute induction of IFNL4 This behavior is evolutionarily conserved and can be reversed by inserting a functional IRF3 binding site into the IFNL4 promoter. Thus, the regulation of the IFNL4 gene is radically different and might explain some of the atypical phenotypes associated with the IFNL4 gene in humans.Importance Recent genetic evidence has highlighted how the IFNL4 gene acts in a counterintuitive manner as patients with a non-functional IFNL4 gene exhibit increased clearance of hepatitis C virus but also increased liver inflammation. This suggests that the IFNL4 gene acts in a pro-viral and anti-inflammatory manner. Those surprising but quite clear genetic data have prompted an extensive examination of the basic characteristics of the IFNL4 gene and its gene product IFN-λ4. We have investigated the expression of the IFNL4 gene and found it to be poorly induced by viral infections. A thorough investigation of the IFNL4 promoter revealed a highly conserved and functional promoter, but also one that lacks the defining characteristic of IFNs, i.e. the ability to be effectively induced by viral infections. We suggest that the unique function of the IFNL4 gene is related to its non-canonical transcriptional regulation.
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