Dephosphorylation of the RNA sensors RIG-I and MDA5 by the phosphatase PP1 is essential for innate immune signaling.
Dephosphorylation of the RNA sensors RIG-I and MDA5 by the phosphatase PP1 is essential for innate immune signaling.
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DOI：
10.1016/j.immuni.2012.11.018
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发表时间：
2013-03-21
期刊：
影响因子：
32.4
通讯作者：
Gack MU
中科院分区：
文献类型：
--
作者：
Wies E;Wang MK;Maharaj NP;Chen K;Zhou S;Finberg RW;Gack MU
RIG-I和MDA5已成为检测RNA病毒的关键胞质传感器，导致抗病毒干扰素(IFN)的产生。最近的研究强调了翻译后修饰对控制RIG-I抗病毒活性的重要性。然而，MDA5信号转导能力的调控仍不清楚。在这里，我们表明MDA5的信号活性是由其CARD结构域的磷酸化和去磷酸化之间的动态平衡调节的。利用磷酸组RNAi筛选，我们确定pp1α和pp1γ是主要的磷酸酶，负责MDA5和RIG-I的去磷酸化，导致它们的激活。沉默pp1α和pp1γ可增强RIG-I和MDA5CARD的磷酸化，减少抗病毒干扰素-β的产生。PP1RNA和PP1RNA缺失的细胞诱导干扰素刺激的基因表达的能力受损，导致α病毒复制增强。本工作确定pp1α和pp1γ是多种RNA病毒，包括流感病毒、副粘病毒、登革热病毒和小核糖核酸病毒的抗病毒天然免疫反应的调节因子。
RIG-I and MDA5 have emerged as key cytosolic sensors for the detection of RNA viruses, leading to antiviral interferon (IFN) production. Recent studies highlighted the importance of posttranslational modification for controlling RIG-I antiviral activity. However, the regulation of MDA5 signal-transducing ability remains unclear. Here we show that MDA5 signaling activity is regulated by a dynamic balance between phosphorylation and dephosphorylation of its CARD domains. Employing a phosphatome RNAi screen, we identified PP1α and PP1γ as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation. Silencing of PP1α and PP1γ enhanced RIG-I and MDA5 CARD phosphorylation and reduced antiviral IFN-β production. PP1α and PP1γ depleted cells were impaired in their ability to induce interferon-stimulated gene expression, which resulted in enhanced RNA virus replication. This work identifies PP1α and PP1γ as regulators of antiviral innate immune responses to various RNA viruses, including influenza virus, paramyxovirus, dengue virus and picornavirus.
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