Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
EMBO J. 2013 Nov 27;32(23):3055-65. doi: 10.1038/emboj.2013.232. Epub 2013 Oct 29.
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 IFNλ4 ORF. The expression of IFNλ4 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 IFNλ4, which signals through the IFNλR1 and IL-10R2 receptor chains. Recombinant IFNλ4 is antiviral against both HCV and coronaviruses at levels comparable to IFNλ3. However, the secretion of IFNλ4 is impaired compared to that of IFNλ3, and this impairment is not due to a weak signal peptide, which was previously believed. We found that IFNλ4 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 IFNλ4 is strongly antiviral but a disadvantage during HCV infection.
IFNL4 基因是一种新近发现的 III 型干扰素，在很大一部分人群中，它携带有一个移码突变，从而破坏了 IFNλ4 的开放阅读框。IFNλ4 的表达与丙型肝炎病毒（HCV）的自发性清除不良和对 I 型干扰素治疗的反应不良密切相关。在这里，我们表明 IFNL4 基因编码一种活性的 III 型干扰素，命名为 IFNλ4，它通过 IFNλR1 和 IL-10R2 受体链发出信号。重组 IFNλ4 对 HCV 和冠状病毒均具有抗病毒活性，其水平可与 IFNλ3 相媲美。然而，与 IFNλ3 相比，IFNλ4 的分泌受到损害，而这种损害并不是由于先前认为的弱信号肽所致。我们发现 IFNλ4 发生 N 连接糖基化，并且这种糖基化是分泌所必需的。尽管如此，这种糖基化对于活性并非必需。这些发现的结果导致了一个悖论，即 IFNλ4 具有很强的抗病毒活性，但在 HCV 感染期间却是一个劣势。
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