Ubiquitin-dependent Turnover of Adenosine Deaminase Acting on RNA 1 (ADAR1) Is Required for Efficient Antiviral Activity of Type I Interferon
Ubiquitin-dependent Turnover of Adenosine Deaminase Acting on RNA 1 (ADAR1) Is Required for Efficient Antiviral Activity of Type I Interferon
复制标题
I 型干扰素的有效抗病毒活性需要作用于 RNA 1 (ADAR1) 的腺苷脱氨酶的泛素依赖性转换
DOI：
10.1074/jbc.m116.737098
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发表时间：
2016-11-25
影响因子：
4.8
通讯作者：
Zheng, Hui
中科院分区：
文献类型：
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作者：
Li, Lemin;Qian, Guanghui;Zheng, Hui
作用于 RNA 1 (ADAR1) 的腺苷脱氨酶可催化细胞和病毒 RNA 的 RNA 编辑。除了 RNA 编辑之外，ADAR1 最近被证明通过抑制 IFN 产生和随后的 IFN 激活途径，在维持身体平衡方面发挥着重要作用，包括组织稳态、器官发育和自身免疫调节。因此，提出了病毒感染诱导的 IFN 信号传导如何克服组成型表达的 ADAR1 (ADAR1-P110) 的抑制作用以执行有效的抗病毒活性的问题。在这里，我们意外地发现IFN信号传导促进Lys(48)连接的ADAR1-P110的泛素化和降解。此外，我们还发现了 E3 连接酶 β 转导蛋白重复序列负责 IFN 介导的 ADAR1-P110 下调。 IFN 信号传导促进含有 β 转导蛋白重复序列的蛋白质与 ADAR1-P110 之间的相互作用以及 ADAR1-P110 的蛋白质周转。此外，我们发现赖氨酸 574 和 576 对于 ADAR1-P110 泛素化都是必需的。至关重要的是，我们证明了 ADAR1-P110 的下调是 IFN 信号传导在病毒感染期间执行有效抗病毒活性所必需的。这些发现重新认识了干扰素信号传导实现抗病毒功能的机制，并可能为基于干扰素的抗病毒治疗提供潜在靶标。
Adenosine deaminase acting on RNA 1 (ADAR1) catalyzes RNA editing of cellular and viral RNAs. Besides RNA editing, ADAR1 has recently been shown to play important roles in maintaining the body balance, including tissue homoeostasis, organ development, and autoimmune regulations, by inhibiting both IFN production and subsequent IFN-activated pathways. Accordingly, the question was raised how IFN signaling induced by viral infections overcomes the inhibitory effect of constitutively expressed ADAR1 (ADAR1-P110) to execute efficient antiviral activity. Here we unexpectedly found that IFN signaling promoted Lys(48)-linked ubiquitination and degradation of ADAR1-P110. Furthermore, we identified the E3 ligase beta transducin repeat-containing protein responsible for IFN-mediated ADAR1-P110 down-regulation. IFN signaling promoted the interaction between beta transducin repeat-containing protein and ADAR1-P110 as well as protein turnover of ADAR1-P110. Moreover, we found that both lysine 574 and 576 are essential for ADAR1-P110 ubiquitination. Critically, we demonstrated that down-regulation of ADAR1-P110 is required for IFN signaling to execute efficient antiviral activity during viral infections. These findings renew the understanding of the mechanisms by which IFN signaling acts to achieve antiviral functions and may provide potential targets for IFN-based antiviral therapy.