DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death.

DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death.
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DOI:
10.1016/j.chom.2016.09.014
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发表时间:
2016-11-09
影响因子:
30.3
通讯作者:
Balachandran S
Balachandran S
中科院分区:
医学1区
文献类型:
--
作者:
Thapa RJ;Ingram JP;Ragan KB;Nogusa S;Boyd DF;Benitez AA;Sridharan H;Kosoff R;Shubina M;Landsteiner VJ;Andrake M;Vogel P;Sigal LJ;tenOever BR;Thomas PG;Upton JW;Balachandran S

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甲型流感病毒(IAV)是一种RNA病毒,对它复制的大多数细胞类型具有细胞毒性。IAV激活宿主激酶RIPK 3,其通过由假激酶MLKL驱动的坏死性凋亡和依赖于衔接蛋白RIPK 1和FADD的凋亡的平行途径诱导细胞死亡。IAV如何激活RIPK 3仍然未知。我们报告说,DAI(ZBP-1/DLM-1),以前牵连作为一个细胞质DNA传感器,是必不可少的RIPK 3激活IAV。在感染后,DAI识别IAV基因组RNA,与RIPK 3缔合,并且是将MLKL和RIPK 1募集到RIPK 3所需的。缺乏DAI或含有核酸结合缺陷的DAI突变体的细胞对IAV触发的坏死性凋亡和凋亡具有抗性。DAI缺陷小鼠不能控制IAV复制,并死于致命的呼吸道感染。这些结果确定DAI作为IAV复制和RIPK 3激活之间的联系,并暗示DAI作为RNA病毒的传感器。
Influenza A virus (IAV) is an RNA virus that is cytotoxic to most cell types in which it replicates. IAV activates the host kinase RIPK3, which induces cell death via parallel pathways of necroptosis, driven by the pseudokinase MLKL, and apoptosis, dependent on the adaptor proteins RIPK1 and FADD. How IAV activates RIPK3 remains unknown. We report that DAI (ZBP-1/DLM-1), previously implicated as a cytoplasmic DNA sensor, is essential for RIPK3 activation by IAV. Upon infection, DAI recognizes IAV genomic RNA, associates with RIPK3, and is required for recruitment of MLKL and RIPK1 to RIPK3. Cells lacking DAI or containing DAI mutants deficient in nucleic acid binding are resistant to IAV-triggered necroptosis and apoptosis. DAI-deficient mice fail to control IAV replication and succumb to lethal respiratory infection. These results identify DAI as a link between IAV replication and RIPK3 activation, and implicate DAI as a sensor of RNA viruses.
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