Discipline of Pharmacology, School of Medical Sciences, University of Sydney, NSW 2006, Australia.
Department of Life Sciences, Imperial College London, South Kensington, SW7 2AZ London, United Kingdom.
Biophys Chem. 2021 Feb;269:106524. doi: 10.1016/j.bpc.2020.106524. Epub 2020 Dec 14.
The viral protein ICP6, encoded by herpes simplex virus 1 (HSV-1), harbours a RIP-homotypic interaction motif (RHIM), that plays a role in viral inhibition of host cell death pathways. Other members of the Herpesviridae family also encode RHIM-containing proteins that interfere with host-cell death pathways, including the M45 protein from murine cytomegalovirus, and ORF20 protein from varicella zoster virus. We have used amyloid assembly assays, electron microscopy and single molecule fluorescence spectroscopy to show that the ICP6 RHIM is amyloidogenic and can interact with host RHIM-containing proteins to form heteromeric amyloid complexes, in a manner similar to that of M45 and ORF20 RHIMs. The core tetrad sequence of the ICP6 RHIM is important for both amyloid formation and interaction with host RHIM-containing proteins. Notably, we show that the amyloid forming capacity of the ICP6 RHIM is affected by the redox environment. We propose that the formation of an intramolecular disulfide bond within ICP6 triggers the formation of amyloid assemblies that are distinct from previously characterised viral amyloids M45 and ORF20. Formation of viral-host heteromeric amyloid assemblies may underlie a general mechanism of viral adaptation against host immune machineries.
单纯疱疹病毒 1（HSV-1）编码的病毒蛋白 ICP6 含有 RIP 同源相互作用基序（RHIM），该基序在病毒抑制宿主细胞死亡途径中发挥作用。疱疹病毒科的其他成员也编码含有 RHIM 的蛋白，这些蛋白干扰宿主细胞的死亡途径，包括鼠巨细胞病毒的 M45 蛋白和水痘带状疱疹病毒的 ORF20 蛋白。我们使用淀粉样蛋白组装测定、电子显微镜和单分子荧光光谱法表明，ICP6 RHIM 具有淀粉样蛋白形成能力，并且可以与宿主含有 RHIM 的蛋白质相互作用形成异源淀粉样蛋白复合物，这种方式类似于 M45 和 ORF20 RHIM。ICP6 RHIM 的核心四联体序列对于淀粉样蛋白形成和与宿主含有 RHIM 的蛋白质相互作用都很重要。值得注意的是，我们表明 ICP6 RHIM 的淀粉样蛋白形成能力受到氧化还原环境的影响。我们提出，ICP6 内形成的分子内二硫键触发了不同于先前表征的病毒淀粉样蛋白 M45 和 ORF20 的淀粉样蛋白组装的形成。病毒-宿主异源淀粉样蛋白组装的形成可能是病毒适应宿主免疫机制的一般机制。
