Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
Center for Predictive Medicine and Emerging Infectious Diseases, University of Louisville, Louisville, KY 40202, USA.
Viruses. 2021 Feb 27;13(3):377. doi: 10.3390/v13030377.
Alphaviruses are arthropod-borne RNA viruses which can cause either mild to severe febrile arthritis which may persist for months, or encephalitis which can lead to death or lifelong cognitive impairments. The non-assembly molecular role(s), functions, and protein-protein interactions of the alphavirus capsid proteins have been largely overlooked. Here we detail the use of a BioID2 biotin ligase system to identify the protein-protein interactions of the Sindbis virus capsid protein. These efforts led to the discovery of a series of novel host-pathogen interactions, including the identification of an interaction between the alphaviral capsid protein and the host IRAK1 protein. Importantly, this capsid-IRAK1 interaction is conserved across multiple alphavirus species, including arthritogenic alphaviruses SINV, Ross River virus, and Chikungunya virus; and encephalitic alphaviruses Eastern Equine Encephalitis virus, and Venezuelan Equine Encephalitis virus. The impact of the capsid-IRAK1 interaction was evaluated using a robust set of cellular model systems, leading to the realization that the alphaviral capsid protein specifically inhibits IRAK1-dependent signaling. This inhibition represents a means by which alphaviruses may evade innate immune detection and activation prior to viral gene expression. Altogether, these data identify novel capsid protein-protein interactions, establish the capsid-IRAK1 interaction as a common alphavirus host-pathogen interface, and delineate the molecular consequences of the capsid-IRAK1 interaction on IRAK1-dependent signaling.
甲病毒是一种节肢动物传播的 RNA 病毒，可以引起轻度至重度发热性关节炎，这种关节炎可能持续数月，也可以引起脑炎，导致死亡或终身认知障碍。甲病毒衣壳蛋白的非组装分子作用、功能和蛋白-蛋白相互作用在很大程度上被忽视了。在这里，我们详细介绍了使用 BioID2 生物素连接酶系统来鉴定辛德毕斯病毒衣壳蛋白的蛋白-蛋白相互作用。这些努力导致发现了一系列新的宿主-病原体相互作用，包括鉴定甲型病毒衣壳蛋白与宿主 IRAK1 蛋白之间的相互作用。重要的是，这种衣壳-IRAK1 相互作用在多种甲病毒种中是保守的，包括致关节炎的甲病毒 SINV、罗斯河病毒和基孔肯雅病毒；以及致脑炎的甲病毒东方马脑炎病毒和委内瑞拉马脑炎病毒。使用一系列强大的细胞模型系统评估了衣壳-IRAK1 相互作用的影响，导致人们认识到甲型病毒衣壳蛋白特异性抑制 IRAK1 依赖性信号。这种抑制作用代表了甲型病毒在病毒基因表达之前逃避先天免疫检测和激活的一种手段。总之，这些数据鉴定了新的衣壳蛋白-蛋白相互作用，确立了衣壳-IRAK1 相互作用作为一种常见的甲病毒宿主-病原体界面，并描述了衣壳-IRAK1 相互作用对 IRAK1 依赖性信号的分子后果。
