A Viral Protein Restricts Drosophila RNAi Immunity by Regulating Argonaute Activity and Stability.
A Viral Protein Restricts Drosophila RNAi Immunity by Regulating Argonaute Activity and Stability.
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DOI：
10.1016/j.chom.2018.09.006
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发表时间：
2018-10-10
影响因子：
30.3
通讯作者：
Andino R
中科院分区：
文献类型：
--
作者：
Nayak A;Kim DY;Trnka MJ;Kerr CH;Lidsky PV;Stanley DJ;Rivera BM;Li KH;Burlingame AL;Jan E;Frydman J;Gross JD;Andino R
蟋蟀麻痹病毒（CrPV）编码RNA干扰（RNAi）抑制因子1A，可调节病毒毒力。利用果蝇模型，我们结合了结构、生化和病毒学方法来阐明CrPV-1A限制RNAi免疫的策略。CrPV-1A的原子分辨率结构揭示了一个与Argonaute 2 （Ago-2）相互作用的柔性环，从而抑制Ago-2内切酶依赖性免疫。破坏ago -2结合的突变减弱了野生型而不是缺乏ago -2的果蝇的病毒发病机制。CrPV-1A还含有一个BC-box基元，使病毒能够劫持宿主Cul2-Rbx1-EloBC泛素连接酶复合物，从而促进Ago-2降解和病毒复制。我们的研究揭示了一个基于病毒的双调控程序，通过与宿主蛋白的直接相互作用和调节来限制抗病毒免疫。虽然直接抑制Ago-2活性提供了建立感染的有效机制，但泛素连接酶复合体的募集使CrPV-1A能够放大Ago-2失活以进一步限制抗病毒RNAi免疫。
The dicistrovirus, Cricket paralysis virus (CrPV) encodes an RNA interference (RNAi) suppressor, 1A, which modulates viral virulence. Using the Drosophila model, we combined structural, biochemical, and virological approaches to elucidate the strategies by which CrPV-1A restricts RNAi immunity. The atomic resolution structure of CrPV-1A uncovered a flexible loop that interacts with Argonaute 2 (Ago-2), thereby inhibiting Ago-2 endonuclease-dependent immunity. Mutations disrupting Ago-2-binding attenuates viral pathogenesis in wild-type but not Ago-2-deficient flies. CrPV-1A also contains a BC-box motif that enables the virus to hijack a host Cul2-Rbx1-EloBC ubiquitin ligase complex, which promotes Ago-2 degradation and virus replication. Our study uncovers a viral-based dual regulatory program that restricts antiviral immunity by direct interaction with and modulation of host proteins. While the direct inhibition of Ago-2 activity provides an efficient mechanism to establish infection, the recruitment of a ubiquitin ligase complex, enables CrPV-1A to amplify Ago-2 inactivation to restrict further antiviral RNAi immunity.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
Desimmie, Belete A.;Delviks-Frankenberrry, Krista A.;Burdick, Ryan C.;Qi, DongFei;Izumi, Taisuke;Pathak, Vinay K.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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通讯作者：
Cowtan, K
影响因子：
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作者：
Kobayashi, M;Takaori-Kondo, A;Uchiyama, T
通讯作者：
Uchiyama, T