MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response.
MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response.
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DOI：
10.1016/j.cell.2011.06.041
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发表时间：
2011-08-05
期刊：
影响因子：
64.5
通讯作者：
Chen ZJ
中科院分区：
文献类型：
--
作者：
Hou F;Sun L;Zheng H;Skaug B;Jiang QX;Chen ZJ
作为对病毒感染的应答，RIG-I类κ解旋酶与病毒核糖核酸结合，激活线粒体蛋白MAVS，进而激活转录因子IRF3和NF-MAVS B诱导I型干扰素。我们先前已经证明RIG-I与未锚定的赖氨酸-63(K63)多泛素链结合，这种结合对于MAV激活是重要的；然而，MAV激活的机制尚不清楚。在这里，我们表明，病毒感染诱导形成非常大的MAV聚集体，这有效地激活了细胞质中的IRF3。我们发现，重组MAVS蛋白的一部分形成了能够激活IRF3的纤维。值得注意的是，小牛纤维的行为类似于普里恩，并有效地将内源性小牛转化为功能聚集体。我们还发现，在K63泛素链存在的情况下，RIG-I催化线粒体膜上的MAV转化为普恩样聚集体。这些结果表明，MAV的一个类病毒构象开关激活并传播了抗病毒信号级联反应。
In response to viral infection, RIG-I–like RNA helicases bind to viral RNA and activate the mitochondrial protein MAVS, which in turn activates the transcription factors IRF3 and NF-κB to induce type-I interferons. We have previously shown that RIG-I binds to unanchored lysine-63 (K63) polyubiquitin chains and that this binding is important for MAVS activation; however, the mechanism underlying MAVS activation is not understood. Here we show that viral infection induces the formation of very large MAVS aggregates, which potently activate IRF3 in the cytosol. We find that a fraction of recombinant MAVS protein forms fibrils capable of activating IRF3. Remarkably, the MAVS fibrils behave like prions and effectively convert endogenous MAVS into functional aggregates. We also show that, in the presence of K63 ubiquitin chains, RIG-I catalyzes the conversion of MAVS on the mitochondrial membrane to prion-like aggregates. These results suggest that a prion-like conformational switch of MAVS activates and propagates the antiviral signaling cascade.
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