Viral infections activate types I and III interferon genes through a common mechanism
Viral infections activate types I and III interferon genes through a common mechanism
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DOI：
10.1074/jbc.m608618200
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发表时间：
2007-03-09
影响因子：
4.8
通讯作者：
Fujita, Takashi
中科院分区：
文献类型：
--
作者：
Onoguchi, Kazuhide;Yoneyama, Mitsutoshi;Fujita, Takashi
病毒感染会引发先天免疫反应，包括 I 型干扰素（IFN-α 和 β）和其他促炎细胞因子的产生。新型抗病毒细胞因子 IFN-lambda 1、IFN-lambda 2 和 IFN-lambda 3 被归类为 III 型 IFN，并且独立于 I 型 IFN 进化。 III型干扰素基因在转录水平上受到调节并由病毒感染诱导。尽管I型IFN的调节机制已被很好地阐明，但IFN-lambda的表达机制尚不清楚。在这里，我们分析了病毒感染诱导 IFN-lambda 基因表达的机制。功能丧失和获得的实验揭示了 RIG-I（视黄酸诱导基因 1）、IPS-1、TBK1 和干扰素调节因子 3（病毒诱导的 I 型 IFN 基因激活的关键调节因子）的参与。与此一致的是，对人 ifn lambda 1 顺式调节元件的研究揭示了一组干扰素调节因子结合位点和 NF-κ B 结合位点。功能分析表明，所有这些位点对于病毒的基因激活都是必需的。这些结果强烈表明 I 型和 III 型 IFN 基因受到共同机制的调节。
Viral infections trigger innate immune responses, including the production of type I interferons (IFN-alpha and -beta) and other proinflammatory cytokines. Novel antiviral cytokines IFN-lambda 1, IFN-lambda 2, and IFN-lambda 3 are classified as type III IFNs and have evolved independently of type I IFNs. Type III IFN genes are regulated at the level of transcription and induced by viral infection. Although the regulatory mechanism of type I IFNs is well elucidated, the expression mechanism of IFN-lambda s is not well understood. Here, we analyzed the mechanism by which IFN-lambda gene expression is induced by viral infections. Loss- and gain-of-function experiments revealed the involvement of RIG-I (retinoic acid-inducible gene 1), IPS-1, TBK1, and interferon regulatory factor-3, key regulators of the virus-induced activation of type I IFN genes. Consistent with this, a search for the cis-regulatory element of the human ifn lambda 1 revealed a cluster of interferon regulatory factor-binding sites and a NF-kappa B-binding site. Functional analysis demonstrated that all of these sites are essential for gene activation by the virus. These results strongly suggest that types I and III IFN genes are regulated by a common mechanism.