Scrima Nathalie, Le Bars Romain, Nevers Quentin, Glon Damien, Chevreux Guillaume, Civas Ahmet, Blondel Danielle, Lagaudrière-Gesbert Cécile, Gaudin Yves
Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette, France.
Institut Jacques Monod, Université de Paris, CNRS, 75013 Paris, France.
Cell Rep. 2023 Jan 31;42(1):111949. doi: 10.1016/j.celrep.2022.111949. Epub 2023 Jan 4.
Viruses must overcome the interferon-mediated antiviral response to replicate and propagate into their host. Rabies virus (RABV) phosphoprotein P is known to inhibit interferon induction. Here, using a global mass spectrometry approach, we show that RABV P binds to TBK1, a kinase located at the crossroads of many interferon induction pathways, resulting in innate immunity inhibition. Mutations of TBK1 phosphorylation sites abolish P binding. Importantly, we demonstrate that upon RABV infection or detection of dsRNA by innate immunity sensors, TBK1 and its adaptor proteins NAP1 and SINTBAD form dynamic cytoplasmic condensates that have liquid properties. These condensates can form larger aggregates having ring-like structures in which NAP1 and TBK1 exhibit locally restricted movement. P binding to TBK1 interferes with the formation of these structures. This work demonstrates that proteins of the signaling pathway leading to interferon induction transiently form liquid organelles that can be targeted by viruses.
病毒必须克服干扰素介导的抗病毒反应才能在其宿主中复制和传播。已知狂犬病病毒（RABV）磷蛋白P可抑制干扰素的诱导。在此，我们使用一种全局质谱方法表明，RABV P与TBK1结合，TBK1是一种位于许多干扰素诱导途径交叉点的激酶，从而导致先天免疫抑制。TBK1磷酸化位点的突变消除了P的结合。重要的是，我们证明，在RABV感染或先天免疫传感器检测到双链RNA后，TBK1及其衔接蛋白NAP1和SINTBAD会形成具有液体特性的动态细胞质凝聚物。这些凝聚物可以形成具有环状结构的更大聚集体，其中NAP1和TBK1表现出局部受限的运动。P与TBK1的结合会干扰这些结构的形成。这项工作表明，导致干扰素诱导的信号通路中的蛋白质会短暂形成液体细胞器，而病毒可以靶向这些细胞器。
