ISG15 enhances the innate antiviral response by inhibition of IRF-3 degradation
ISG15 enhances the innate antiviral response by inhibition of IRF-3 degradation
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DOI：
10.1170/t695
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发表时间：
2006-01-01
影响因子：
1.6
通讯作者：
Pitha, P. M.
中科院分区：
文献类型：
--
作者：
Lu, G.;Reinert, J. T.;Pitha, P. M.
转录因子干扰素调节因子3（IRF-3）在抗病毒先天免疫应答的激活中起关键作用。然而，IRF-3的转录活性受到蛋白体介导的降解的严格调控。我们在这里描述了一种新的机制，通过这种机制，IRF-3的活性在感染的细胞中得到稳定。我们已经表明，干扰素治疗和NDV感染都显著增加了干扰素诱导的泛素样蛋白ISG 15与细胞蛋白的结合。ISGylated IRF-3在干扰素处理的和病毒感染的细胞中都可以检测到。ISG 15在NDV感染的2fTGH细胞中破坏了泛素介导的IRF-3降解，并增强了NDV介导的干扰素β启动子的反式激活和活化的IRF-3向细胞核的移位。在NDV感染的ISG 15 null MEF中，IRF-3的相对水平显著低于wt MEF。虽然ISG 15无效MEF更允许VSV复制，但它们对干扰素的抗病毒作用的敏感性不受调节。这些结果表明，病毒介导的IRF-3蛋白水解破坏抗病毒应答被ISG 15表达的诱导抵消，ISG 15化提供了一种反馈机制，通过IRF-3稳定增强宿主先天性抗病毒应答。
The transcription factor, interferon regulatory Factor 3 (IRF-3) plays a critical role in the activation of an antiviral innate immune response. However the transcriptional activity of IRF-3 is tightly regulated by a proteosome mediated degradation. We describe here a novel mechanism by which the activity of IRF-3 is stabilized in infected cells. We have shown that both interferon treatment and NDV infection profoundly increase conjugation of interferon induced ubiquitin-like protein ISG15 to cellular proteins. ISGylated IRF-3 could be detected both in interferon treated and virus-infected cells. ISG15 subverts the ubiquitin mediated degradation of IRF-3 in NDV infected 2fTGH cells and enhances the NDV mediated transactivation of interferon beta promoter and the translocation of activated IRF-3 to the nucleus. The relative levels of IRF-3 were significantly lower in NDV infected ISG15 null MEF, than in wt MEF. While ISG15 null MEF were more permissive to VSV replication their sensitivity to the antiviral effect of interferon was not modulated. These results reveal that virus mediated subversion of the antiviral response by proteolysis of IRF-3 is counteracted by induction of ISG15 expression and that ISGylation provides a feedback mechanism, which enhances the host innate antiviral response via IRF-3 stabilization.