Interferon lambda 4 expression is suppressed by the host during viral infection
Interferon lambda 4 expression is suppressed by the host during viral infection
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DOI：
10.1084/jem.20160437
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发表时间：
2016-11-01
影响因子：
15.3
通讯作者：
Savan, Ram
中科院分区：
文献类型：
--
作者：
Hong, MeeAe;Schwerk, Johannes;Savan, Ram
干扰素是肝脏和粘膜感染的关键抗病毒效应物。尽管干扰素lambda 1、干扰素lambda 2和干扰素lambda 3具有抗病毒作用，但遗传关联研究表明，最近发现的IFNL4的表达通过一种未知的机制对丙型肝炎病毒(HCV)感染有害。有趣的是，人类的IFNL4含有一种基因变异，这种变异会导致过早终止密码子。我们对干扰素lambda 4进行了分子和生化鉴定，以确定其作用和表达调控。我们发现，干扰素lambda 4具有与干扰素lambda 3相似的抗病毒活性，而不会对抗病毒干扰素活性或细胞存活产生负面影响。我们发现，人类通过非编码剪接变异体和非功能蛋白亚型来限制功能性干扰素lambda 4的表达。此外，编码蛋白质的IFNL4 mRNA不能装载到多聚核糖体上，缺乏很强的多聚腺苷信号，导致翻译效率较低。这项研究提供了人类抑制干扰素lambda 4表达的机制证据，表明免疫功能依赖于IFNL家族的其他成员。
Interferon (IFN) lambdas are critical antiviral effectors in hepatic and mucosal infections. Although IFN lambda 1, IFN lambda 2, and IFN lambda 3 act antiviral, genetic association studies have shown that expression of the recently discovered IFNL4 is detrimental to hepatitis C virus (HCV) infection through a yet unknown mechanism. Intriguingly, human IFNL4 harbors a genetic variant that introduces a premature stop codon. We performed a molecular and biochemical characterization of IFN lambda 4 to determine its role and regulation of expression. We found that IFN lambda 4 exhibits similar antiviral activity to IFN lambda 3 without negatively affecting antiviral IFN activity or cell survival. We show that humans deploy several mechanisms to limit expression of functional IFN lambda 4 through noncoding splice variants and nonfunctional protein isoforms. Furthermore, protein-coding IFNL4 mRNA are not loaded onto polyribosomes and lack a strong polyadenylation signal, resulting in poor translation efficiency. This study provides mechanistic evidence that humans suppress IFN lambda 4 expression, suggesting that immune function is dependent on other IFNL family members.