Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Cell. 2011 Aug 5;146(3):448-61. doi: 10.1016/j.cell.2011.06.041. Epub 2011 Jul 21.
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. [corrected] 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 that are 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.
针对病毒感染，RIG-I 样 RNA 解旋酶与病毒 RNA 结合，并激活线粒体蛋白 MAVS，而 MAVS 又反过来激活转录因子 IRF3 和 NF-κB，诱导 I 型干扰素的产生。[更正]我们之前已经表明，RIG-I 与非锚定赖氨酸-63（K63）多聚泛素链结合，这种结合对于 MAVS 的激活很重要；然而，MAVS 激活的机制尚不清楚。在这里，我们表明病毒感染诱导形成了非常大的 MAVS 聚集体，这些聚集体在细胞质中强烈激活 IRF3。我们发现，重组 MAVS 蛋白的一部分形成原纤维，能够激活 IRF3。值得注意的是，MAVS 原纤维的行为类似于朊病毒，并有效地将内源性 MAVS 转化为功能性聚集体。我们还表明，在 K63 泛素链存在的情况下，RIG-I 可催化线粒体膜上 MAVS 的转化为朊病毒样聚集体。这些结果表明，MAVS 的朊病毒样构象转换激活并传播抗病毒信号级联。
