Rotavirus NSP1 inhibits expression of type I interferon by antagonizing the function of interferon regulatory factors IRF3, IRF5, and IRF7
Rotavirus NSP1 inhibits expression of type I interferon by antagonizing the function of interferon regulatory factors IRF3, IRF5, and IRF7
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DOI：
10.1128/jvi.02498-06
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发表时间：
2007-05-01
影响因子：
5.4
通讯作者：
Patton, John T.
中科院分区：
文献类型：
--
作者：
Barro, Mario;Patton, John T.
受病毒感染的细胞分泌干扰素（IFN）对于激活自分泌和旁分泌途径至关重要，从而促进细胞向抗病毒状态转变。在大多数哺乳动物细胞中，IFN的产生是由组成性表达的IFN调节因子3 IRF3的激活启动的，IRF3反过来又导致IRF7的诱导，IRF7是IFN I型合成（α / β IFN）的“主调节器”。先前的研究证实轮状病毒NSP1通过诱导IRF3降解来拮抗IFN信号。在目前的研究中，我们已经确定，与野生型轮状病毒相比，编码有缺陷的NSP1的轮状病毒在一些细胞系中生长到较低的滴度，这种不良的生长表型是由于它们不能抑制IFN的表达。此外，我们提供的证据表明，编码野生型NSP1的轮状病毒通过诱导IRF3和IRF7的降解来破坏IFN信号，这两种事件都是通过蛋白酶体依赖性过程发生的，其效率相似。NSP1诱导IRF7降解的能力可能允许轮状病毒通过使病毒在组成性表达IRF7的特化运输细胞（树突状细胞和巨噬细胞）中复制而穿过肠道屏障。与IRF3和IRF7一起，NSP1被发现诱导IRF5的降解，IRF5是一种上调IFN表达的因子，在病毒感染期间参与触发细胞凋亡。我们的分析表明，NSP1通过识别IRF蛋白的一个共同元素来介导IRF3、IRF5和IRF7的降解，从而使NSP1作为IRF功能的广谱拮抗剂。
Secretion of interferon (IFN) by virus-infected cells is essential for activating autocrine and paracrine pathways that promote cellular transition to an antiviral state. In most mammalian cells, IFN production is initiated by the activation of constitutively expressed IFN regulatory factor 3, IRF3, which in turn leads to the induction of IRF7, the "master regulator" of IFN type I synthesis (alpha/beta IFN). Previous studies established that rotavirus NSP1 antagonizes IFN signaling by inducing IRF3 degradation. In the present study, we have determined that, in comparison to wild-type rotaviruses, rotaviruses encoding defective NSP1 grow to lower titers in some cell lines and that this poor growth phenotype is due to their failure to suppress IFN expression. Furthermore, we provide evidence that rotaviruses encoding wild-type NSP1 subvert IFN signaling by inducing the degradation of not only IRF3, but also IRF7, with both events occurring through proteasome-dependent processes that proceed with similar efficiencies. The capacity of NSP1 to induce IRF7 degradation may allow rotavirus to move across the gut barrier by enabling the virus to replicate in specialized trafficking cells (dendritic cells and macrophages) that constitutively express IRF7. Along with IRF3 and IRF7, NSP1 was found to induce the degradation of IRF5, a factor that upregulates IFN expression and that is involved in triggering apoptosis during viral infection. Our analysis suggests that NSP1 mediates the degradation of IRF3, IRF5, and IRF7 by recognizing a common element of IRF proteins, thereby allowing NSP1 to act as a broad-spectrum antagonist of IRF function.