Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense
Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense
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DOI：
10.1073/pnas.1004621107
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发表时间：
2010-09-07
影响因子：
11.1
通讯作者：
Shimotohno, Kunitada
中科院分区：
文献类型：
--
作者：
Arimoto, Kei-ichiro;Funami, Kenji;Shimotohno, Kunitada
I型IFN的快速诱导是先天防御病毒感染的核心事件，并受到许多细胞分子的严格调节。病毒成分通过激活toll样受体（TLRs）和胞内细胞质受体（如RNA解旋酶rig - 1和/或MDA5）诱导强烈的I型IFN反应。根据最近的研究，nf - κ B必需调节剂（NEMO，也称为IKK γ）对这种病毒诱导的抗病毒反应至关重要。然而，NEMO适配器激活信号的确切作用尚未阐明。在这里，我们发现病毒诱导的IRF3和NF-kappa B的激活依赖于新的泛素E3连接酶triparite motif蛋白23 （TRIM23）对NEMO的K(lys)-27连锁多泛素化。在TRIM23敲低细胞中，病毒诱导的IRF3和NF-kappa B激活以及k27连锁的NEMO多泛素化被消除，而TRIM23敲低对TNF α介导的NF-kappa B激活没有影响。此外，在NEMO缺失的小鼠胚胎成纤维细胞中，正如预期的那样，通过异位表达WT NEMO可以恢复ifn刺激的反应元件驱动的报告细胞活性，但通过NEMO K165/309/325/326/344R多点突变体，trim23介导的泛素偶联性大幅降低，只能部分恢复。因此，我们得出结论，trim23介导的泛素与NEMO结合对于TLR3-和rig - 1 / mda5介导的抗病毒先天和炎症反应是必不可少的。
The rapid induction of type I IFN is a central event of the innate defense against viral infections and is tightly regulated by a number of cellular molecules. Viral components induce strong type I IFN responses through the activation of toll-like receptors (TLRs) and intracellular cytoplasmic receptors such as an RNA helicase RIG-I and/or MDA5. According to recent studies, the NF-kappa B essential modulator (NEMO, also called IKK gamma) is crucial for this virus-induced antiviral response. However, the precise roles of signal activation by NEMO adaptor have not been elucidated. Here, we show that virus-induced IRF3 and NF-kappa B activation depends on the K(lys)-27-linked polyubiquitination to NEMO by the novel ubiquitin E3 ligase triparite motif protein 23 (TRIM23). Virus-induced IRF3 and NF-kappa B activation, as well as K27-linked NEMO polyubiquitination, were abrogated in TRIM23 knockdown cells, whereas TRIM23 knockdown had no effect on TNF alpha-mediated NF-kappa B activation. Furthermore, in NEMO-deficient mouse embryo fibroblast cells, IFN-stimulated response element-driven reporter activity was restored by ectopic expression of WT NEMO, as expected, but only partial recovery by NEMO K165/309/325/326/344R multipoints mutant on which TRIM23-mediated ubiquitin conjugation was substantially reduced. Thus, we conclude that TRIM23-mediated ubiquitin conjugation to NEMO is essential for TLR3- and RIG-I/MDA5-mediated antiviral innate and inflammatory responses.