Despite their role as innate sentinels, macrophages can serve as cellular reservoirs of chikungunya virus (CHIKV), a highly-pathogenic arthropod-borne alphavirus that has caused large outbreaks among human populations. Here, with the use of viral chimeras and evolutionary selection analysis, we define CHIKV glycoproteins E1 and E2 as critical for virion production in THP-1 derived human macrophages. Through proteomic analysis and functional validation, we further identify signal peptidase complex subunit 3 (SPCS3) and eukaryotic translation initiation factor 3 subunit K (eIF3k) as E1-binding host proteins with anti-CHIKV activities. We find that E1 residue V220, which has undergone positive selection, is indispensable for CHIKV production in macrophages, as its mutation attenuates E1 interaction with the host restriction factors SPCS3 and eIF3k. Finally, we show that the antiviral activity of eIF3k is translation-independent, and that CHIKV infection promotes eIF3k translocation from the nucleus to the cytoplasm, where it associates with SPCS3. These functions of CHIKV glycoproteins late in the viral life cycle provide a new example of an intracellular evolutionary arms race with host restriction factors, as well as potential targets for therapeutic intervention.

中文翻译：

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基孔肯雅热病毒糖蛋白与巨噬细胞因子的相互作用控制病毒粒子的产生。


尽管巨噬细胞是先天前哨兵，但它们可以作为基孔肯雅热病毒 （CHIKV） 的细胞储存库，CHIKV 是一种高致病性节肢动物传播的甲病毒，已在人类人群中引起大规模爆发。在这里，通过使用病毒嵌合体和进化选择分析，我们将 CHIKV 糖蛋白 E1 和 E2 定义为对 THP-1 衍生的人巨噬细胞中病毒粒子产生至关重要。通过蛋白质组学分析和功能验证，我们进一步鉴定信号肽酶复合物亚基 3 （SPCS3） 和真核翻译起始因子 3 亚基 K （eIF3k） 作为具有抗 CHIKV 活性的 E1 结合宿主蛋白。我们发现，经过正向选择的 E1 残基 V220 对于巨噬细胞中 CHIKV 的产生是必不可少的，因为它的突变减弱了 E1 与宿主限制因子 SPCS3 和 eIF3k 的相互作用。最后，我们表明 eIF3k 的抗病毒活性是翻译非依赖性的，并且 CHIKV 感染促进 eIF3k 从细胞核到细胞质的易位，在那里它与 SPCS3 结合。CHIKV 糖蛋白在病毒生命周期后期的这些功能为与宿主限制因子的细胞内进化军备竞赛提供了一个新例子，以及治疗干预的潜在靶点。