Hepatitis C virus reveals a novel early control in acute immune response.
Hepatitis C virus reveals a novel early control in acute immune response.
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DOI：
10.1371/journal.ppat.1002289
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发表时间：
2011-10
期刊：
影响因子：
6.7
通讯作者：
Meurs EF
中科院分区：
文献类型：
--
作者：
Arnaud N;Dabo S;Akazawa D;Fukasawa M;Shinkai-Ouchi F;Hugon J;Wakita T;Meurs EF
通过胞质内RNA解旋酶RIG-I识别病毒RNA结构触发先天免疫的诱导。有效的诱导需要E3连接酶TRIM 25的RIG-I泛素化，其与MAVS蛋白的相互作用，TRAF 3、IRF 3和NF-κ B激酶的募集以及干扰素（IFN）的转录。此外，IRF 3单独诱导一些干扰素刺激基因（ISG），称为早期ISG。丙型肝炎病毒（HCV）感染肝细胞导致IFN的产生不足，尽管RIG-I识别病毒RNA，但可导致诱导早期ISG。HCV通过其NS 3/4A蛋白酶切割MAVS和通过激活PKR（一种含有dsRNA结合结构域（DRBD）的eIF 2 α激酶）控制细胞翻译来抑制IFN的产生。在这里，我们已经确定了第三种模式的控制干扰素诱导的HCV。使用HCV-I和Huh7.25.CD81细胞，我们发现HCV通过双泛素样蛋白ISG 15（早期ISG之一）控制RIG-I泛素化。对PKR沉默或未沉默并感染JFH 1的Huh7.25.CD81细胞进行的转录组分析显示，HCV感染导致诱导49个PKR依赖性基因，包括ISG 15和几个早期ISG。沉默实验表明，这种新的PKR依赖性途径涉及MAVS，TRAF 3和IRF 3，但不RIG-I，它不诱导IFN。PKR抑制剂的使用表明，该途径需要DRBD，但不需要PKR的激酶活性。然后，我们证明了PKR与HCV RNA和MAVS的相互作用先于RIG-I。总之，HCV在感染早期招募PKR作为传感器来触发几个IRF 3依赖性基因的诱导。其中，ISG 15在RIG-I泛素化水平上对RIG-I/MAVS通路起负调控作用。丙型肝炎病毒（HCV）是一种弱干扰素（IFN）诱导剂，尽管其RNA被胞质RNA解旋酶RIG-I识别。这部分是由于HCV NS 3/4A蛋白酶切割MAVS（RIG-I的下游衔接子）以及激活eIF 2 α-激酶PKR以控制IFN翻译。在这里，我们表明，HCV还通过泛素样蛋白ISG 15抑制RIG-I激活，并且HCV通过一种新的信号通路触发包括ISG 15在内的49个基因的快速诱导，该信号通路先于RIG-I并涉及PKR作为适配器来招募MAVS。因此，我们建议将对HCV感染的急性反应分为一个早期（PKR）和一个晚期（RIG-I）阶段，前者控制后者。此外，这些数据强调了在使用它们来维持先天免疫之前，需要检查被设计为免疫佐剂的化合物用于激活早期急性期。
Recognition of viral RNA structures by the intracytosolic RNA helicase RIG-I triggers induction of innate immunity. Efficient induction requires RIG-I ubiquitination by the E3 ligase TRIM25, its interaction with the mitochondria-bound MAVS protein, recruitment of TRAF3, IRF3- and NF-κB-kinases and transcription of Interferon (IFN). In addition, IRF3 alone induces some of the Interferon-Stimulated Genes (ISGs), referred to as early ISGs. Infection of hepatocytes with Hepatitis C virus (HCV) results in poor production of IFN despite recognition of the viral RNA by RIG-I but can lead to induction of early ISGs. HCV was shown to inhibit IFN production by cleaving MAVS through its NS3/4A protease and by controlling cellular translation through activation of PKR, an eIF2α-kinase containing dsRNA-binding domains (DRBD). Here, we have identified a third mode of control of IFN induction by HCV. Using HCVcc and the Huh7.25.CD81 cells, we found that HCV controls RIG-I ubiquitination through the di-ubiquitine-like protein ISG15, one of the early ISGs. A transcriptome analysis performed on Huh7.25.CD81 cells silenced or not for PKR and infected with JFH1 revealed that HCV infection leads to induction of 49 PKR-dependent genes, including ISG15 and several early ISGs. Silencing experiments revealed that this novel PKR-dependent pathway involves MAVS, TRAF3 and IRF3 but not RIG-I, and that it does not induce IFN. Use of PKR inhibitors showed that this pathway requires the DRBD but not the kinase activity of PKR. We then demonstrated that PKR interacts with HCV RNA and MAVS prior to RIG-I. In conclusion, HCV recruits PKR early in infection as a sensor to trigger induction of several IRF3-dependent genes. Among those, ISG15 acts to negatively control the RIG-I/MAVS pathway, at the level of RIG-I ubiquitination.These data give novel insights in the machinery involved in the early events of innate immune response. Hepatitis C Virus (HCV) is a poor interferon (IFN) inducer, despite recognition of its RNA by the cytosolic RNA helicase RIG-I. This is due in part through cleavage of MAVS, a downstream adapter of RIG-I, by the HCV NS3/4A protease and through activation of the eIF2α-kinase PKR to control IFN translation. Here, we show that HCV also inhibits RIG-I activation through the ubiquitin-like protein ISG15 and that HCV triggers rapid induction of 49 genes, including ISG15, through a novel signaling pathway that precedes RIG-I and involves PKR as an adapter to recruit MAVS. Hence, we propose to divide the acute response to HCV infection into one early (PKR) and one late (RIG-I) phase, with the former controlling the latter. Furthermore, these data emphazise the need to check compounds designed as immune adjuvants for activation of the early acute phase before using them to sustain innate immunity.
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DOI：
10.1016/s0006-291x(03)01318-4
发表时间：
2003-08-15
影响因子：
3.1
作者：
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通讯作者：
Beal, PA
DOI：
10.1073/pnas.82.13.4341
发表时间：
1985-01-01
影响因子：
11.1
作者：
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通讯作者：
HOVANESSIAN, AG
影响因子：
5.4
作者：
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通讯作者：
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影响因子：
13.5
作者：
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DOI：
10.1016/j.bbadis.2010.02.006
发表时间：
2010-05
期刊：
Biochimica et biophysica acta
影响因子：
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作者：
Jeon YJ;Yoo HM;Chung CH
通讯作者：
Chung CH