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HIV corruption of the Arp2/3-Cdc42-IQGAP1 axis to hijack cortical F-Actin to promote cell-cell viral spread
bioRxiv - Microbiology Pub Date : 2021-09-16 , DOI: 10.1101/2019.12.13.873612
Anupriya Aggarwal , Alberto Ospina Stella , Catherine Henry , Kedar Narayan , Stuart G. Turville

F-Actin remodelling is important for the spread of HIV via cell-cell contacts, yet the mechanisms by which HIV corrupts the actin cytoskeleton are poorly understood. Through live cell imaging and focused ion beam scanning electron microscopy (FIB-SEM), we observed F-Actin structures that exhibit strong positive curvature to be enriched for HIV buds. Virion proteomics, gene silencing, and viral mutagenesis supported a Cdc42-IQGAP1-Arp2/3 pathway as the primary intersection of HIV budding, membrane curvature and F-Actin regulation. Whilst HIV egress activated the Cdc42-Arp2/3 filopodial pathway, this came at the expense of cell-free viral release. Importantly, release could be rescued by cell-cell contact, provided Cdc42 and IQGAP1 were present. From these observations we conclude that a proportion out-going HIV has corrupted a central F-Actin node that enables initial coupling of HIV buds to cortical F-Actin to place HIV at the leading cell edge. Whilst this initially prevents particle release, maturation of cell-cell contacts signals back to this F-Actin node to enable viral release & subsequent infection of the contacting cell.

中文翻译:

HIV 破坏 Arp2/3-Cdc42-IQGAP1 轴以劫持皮质 F-肌动蛋白以促进细胞间病毒传播

F-肌动蛋白重塑对于通过细胞-细胞接触传播的 HIV 很重要,但人们对 HIV 破坏肌动蛋白细胞骨架的机制知之甚少。通过活细胞成像和聚焦离子束扫描电子显微镜 (FIB-SEM),我们观察到 F-肌动蛋白结构表现出强烈的正曲率,以丰富 HIV 芽。病毒蛋白组学、基因沉默和病毒诱变支持 Cdc42-IQGAP1-Arp2/3 通路作为 HIV 萌芽、膜曲率和 F-肌动蛋白调节的主要交叉点。虽然 HIV 流出激活了 Cdc42-Arp2/3 丝状伪足通路,但这是以无细胞病毒释放为代价的。重要的是,只要存在 Cdc42 和 IQGAP1,就可以通过细胞间接触来挽救释放。根据这些观察,我们得出结论,一部分流出的 HIV 已经破坏了中央 F-肌动蛋白节点,该节点使 HIV 芽与皮质 F-肌动蛋白初始偶联,从而将 HIV 置于细胞前沿。虽然这最初会阻止颗粒释放,但细胞-细胞接触的成熟将信号返回到该 F-肌动蛋白节点,以实现病毒释放和接触细胞的后续感染。
更新日期:2021-09-19
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