Institut Pasteur, Unité Dynamique des Lyssavirus et Adaptation à l'Hôte, 25 rue du docteur Roux, 75015 Paris, France.
Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, rue du docteur Roux, 75015 Paris, France.
Sci Rep. 2016 Dec 21;6:39420. doi: 10.1038/srep39420.
The matrix (M) protein of wild isolates of rabies virus such as Tha (M-Tha) was previously shown to be able to interact with RelAp43, a protein of the NF-κB family, and to efficiently suppress NF-κB-dependent reporter gene expression, in contrast with the vaccine strain SAD. Here, we analyze the mechanisms involved in RelAp43-M protein interaction. We demonstrate that the central part of M-Tha, and the specific C-terminal region of RelAp43 are required for this interaction. Four differences in the corresponding amino acid sequences of the M-Tha and M-SAD are shown to be crucial for RelAp43 interaction and subsequent modulation of innate immune response. Furthermore, the capacity of M-Tha to interact with RelAp43 was shown to be crucial for the control of the expression of four genes (IFN, TNF, IL8 and CXCL2) during viral infection. These findings reveal that RelAp43 is a potent regulator of transcription of genes involved in innate immune response during rabies virus infection and that the M protein of wild isolates of rabies virus is a viral immune-modulatory factor playing an important role in this RelAp43-mediated host innate immunity response in contrast to M protein of vaccine strains, which have lost this property.
野生型狂犬病病毒(如 Tha 株,M-Tha)的基质蛋白(M 蛋白)先前被证明能够与 NF-κB 家族的 RelAp43 蛋白相互作用,并有效地抑制 NF-κB 依赖性报告基因表达,这与疫苗株 SAD 不同。在这里,我们分析了 RelAp43-M 蛋白相互作用所涉及的机制。我们证明 M-Tha 的中心部分和 RelAp43 的特定 C 末端区域是这种相互作用所必需的。M-Tha 和 M-SAD 相应氨基酸序列中的四个差异被证明对 RelAp43 相互作用和随后的固有免疫反应的调节至关重要。此外,M-Tha 与 RelAp43 相互作用的能力对于控制病毒感染期间四个基因(IFN、TNF、IL8 和 CXCL2)的表达是至关重要的。这些发现揭示了 RelAp43 是狂犬病病毒感染期间固有免疫反应相关基因转录的一个强有力的调节剂,而野生型狂犬病病毒的 M 蛋白是一种病毒免疫调节因子,在这种 RelAp43 介导的宿主固有免疫反应中发挥重要作用,而疫苗株的 M 蛋白已经失去了这种特性。