The <i>IFNL4</i> Gene Is a Noncanonical Interferon Gene with a Unique but Evolutionarily Conserved Regulation

Abstract

Interferon lambda 4 (IFN-λ4) is a recently identified enigmatic member of the interferon (IFN) lambda family. Genetic data suggest that the <i>IFNL4</i> gene acts in a proviral and anti-inflammatory manner in patients. However, the protein is indistinguishable <i>in vitro</i> from the other members of the interferon lambda family. We have investigated the gene regulation of <i>IFNL4</i> 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 <i>IFNL4</i> This behavior is evolutionarily conserved and can be reversed by inserting a functional IRF3 binding site into the <i>IFNL4</i> promoter. Thus, the regulation of the <i>IFNL4</i> gene is radically different and might explain some of the atypical phenotypes associated with the <i>IFNL4</i> gene in humans.<b>IMPORTANCE</b> Recent genetic evidence has highlighted how the <i>IFNL4</i> gene acts in a counterintuitive manner, as patients with a nonfunctional <i>IFNL4</i> gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation. This suggests that the <i>IFNL4</i> gene acts in a proviral and anti-inflammatory manner. These surprising but quite clear genetic data have prompted an extensive examination of the basic characteristics of the <i>IFNL4</i> gene and its gene product, interferon lambda 4 (IFN-λ4). We have investigated the expression of the <i>IFNL4</i> gene and found it to be poorly induced by viral infections. A thorough investigation of the <i>IFNL4</i> promoter revealed a highly conserved and functional promoter, but also one that lacks the defining characteristic of interferons (IFNs), i.e., the ability to be effectively induced by viral infections. We suggest that the unique function of the <i>IFNL4</i> gene is related to its noncanonical transcriptional regulation.