Interferon lambda 4 signals via the IFNλ receptor to regulate antiviral activity against HCV and coronaviruses

The IFNL4 gene is a recently discovered type III interferon, which in a significant fraction of the human population harbours a frameshift mutation abolishing the IFN lambda 4 ORF. The expression of IFN lambda 4 is correlated with both poor spontaneous clearance of hepatitis C virus (HCV) and poor response to treatment with type I interferon. Here, we show that the IFNL4 gene encodes an active type III interferon, named IFN lambda 4, which signals through the IFN lambda R1 and IL-10R2 receptor chains. Recombinant IFN lambda 4 is antiviral against both HCV and coronaviruses at levels comparable to IFN lambda 3. However, the secretion of IFN lambda 4 is impaired compared to that of IFN lambda 3, and this impairment is not due to a weak signal peptide, which was previously believed. We found that IFN lambda 4 gets N-linked glycosylated and that this glycosylation is required for secretion. Nevertheless, this glycosylation is not required for activity. Together, these findings result in the paradox that IFN lambda 4 is strongly antiviral but a disadvantage during HCV infection.