Poxviruses package viral redox proteins in lateral bodies and modulate the host oxidative response.
Poxviruses package viral redox proteins in lateral bodies and modulate the host oxidative response.
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痘病毒将病毒氧化还原蛋白包装在侧体中并调节宿主的氧化反应。
DOI：
10.1371/journal.ppat.1010614
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发表时间：
2022-07
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
所有痘病毒都含有一组称为侧体（LB）的蛋白质结构，其在病毒进入期间将病毒效应蛋白递送到宿主细胞质中。迄今为止，LB的空间蛋白质型仍然未知。使用原型痘病毒，牛痘病毒（VACV），我们采用定量比较质谱策略来确定痘病毒LB蛋白质组。我们鉴定了大量的候选细胞蛋白，其中大多数是线粒体蛋白，以及15种候选病毒LB蛋白。引人注目的是，其中三分之一是VACV氧化还原蛋白，其LB驻留可以使用超分辨率显微镜确认。我们发现，VACV感染对宿主细胞产生抗氧化作用，人工诱导氧化应激影响早期和晚期基因表达以及病毒体产生。使用靶向阻遏和/或缺失病毒，我们发现单个LB-氧化还原蛋白的缺失不足以进行宿主氧化还原调节，这表明可能存在功能冗余。除了定义VACV LB的空间蛋白质型，这些研究结果暗示痘病毒氧化还原蛋白作为宿主氧化抗病毒反应的潜在调节剂，并为将来研究LB常驻蛋白在宿主免疫调节中的作用提供了坚实的起点。牛痘病毒是痘病毒科的原型成员，其成员包括猴痘和天花病毒，天花的病原体。所有痘病毒颗粒，包括牛痘，都是大而复杂的，含有70多种不同的病毒蛋白。病毒体由3种主要的病毒亚结构组成：容纳病毒基因组的核心，被认为递送宿主调节蛋白的两个蛋白质侧体，以及含有病毒结构、结合和进入所需蛋白质的病毒膜。虽然VACV核心和膜的蛋白质组成是众所周知的，但由于技术原因，存在于侧体中的病毒和细胞蛋白的集合仍然不确定。在这里，我们使用了受控颗粒降解和定量比较质谱的组合来鉴定病毒和细胞候选侧体蛋白。这揭示了用于未来分析的候选侧体细胞和病毒蛋白的大纲要，并揭示了病毒氧化还原蛋白作为潜在的新一类痘病毒免疫调节剂，其通过侧体递送至宿主细胞。
All poxviruses contain a set of proteinaceous structures termed lateral bodies (LB) that deliver viral effector proteins into the host cytosol during virus entry. To date, the spatial proteotype of LBs remains unknown. Using the prototypic poxvirus, vaccinia virus (VACV), we employed a quantitative comparative mass spectrometry strategy to determine the poxvirus LB proteome. We identified a large population of candidate cellular proteins, the majority being mitochondrial, and 15 candidate viral LB proteins. Strikingly, one-third of these are VACV redox proteins whose LB residency could be confirmed using super-resolution microscopy. We show that VACV infection exerts an anti-oxidative effect on host cells and that artificial induction of oxidative stress impacts early and late gene expression as well as virion production. Using targeted repression and/or deletion viruses we found that deletion of individual LB-redox proteins was insufficient for host redox modulation suggesting there may be functional redundancy. In addition to defining the spatial proteotype of VACV LBs, these findings implicate poxvirus redox proteins as potential modulators of host oxidative anti-viral responses and provide a solid starting point for future investigations into the role of LB resident proteins in host immunomodulation. Vaccinia virus is the prototype member of the Poxviridae family, whose members include monkeypox and variola virus, the causative agent of smallpox. All poxvirus particles, including vaccinia, are large and complex containing upwards of 70 different viral proteins. Virions are composed of 3 main viral sub-structures: cores which house the viral genome, two proteinaceous lateral bodies thought to deliver host modulatory proteins, and the viral membrane that harbors proteins required for virus structure, binding and entry. While the protein composition of VACV cores and membranes is well known, for technical reasons the collection of viral and cell proteins that reside in lateral bodies remains undefined. Here, we used a combination of controlled particle degradation and quantitative comparative mass spectrometry to identify viral and cellular candidate lateral body proteins. This revealed a large compendium of candidate lateral body cell and viral proteins for future analysis and uncovered viral redox proteins as a potential new class of poxvirus immunomodulators that are delivered to host cells via lateral bodies.
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