Molecular Mechanism of Action of the Influenza PA-X Host Shutoff Protein

流感 PA-X 宿主关闭蛋白的分子机制

基本信息

  • 批准号:
    10381706
  • 负责人:
  • 金额:
    $ 39.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-05-25 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

Project summary. The innate immune and inflammatory response to influenza A virus is a major contributor to influenza disease, because it promotes viral pneumonia and secondary infections through lung damage. As a consequence, it has recently become clear that blocking influenza virus replication is not sufficient to treat influenza disease. New strategies to block the innate immune and inflammatory responses need to be developed. These strategies could take advantage of the role of viral proteins in modulating host responses, including the host shutoff factor PA-X, which targets host RNAs for degradation. PA-X inhibits immune responses, and viruses that lack PA-X trigger stronger cytokine responses in mouse and chicken infection models. However, these stronger responses do not promote clearance, but in many cases result in increased morbidity and mortality. This indicates that PA-X has a different function from other influenza immune modulators, and that PA-X can be protective for the host. Defining the mechanism of action of PA-X will be important to understand the unique contribution of PA-X to virus-host interplay and to exploit it to modulate host responses to influenza. While host shutoff factors are usually considered indiscriminate, we have found that PA-X is selective, and targets specific types of RNAs. Particularly, we have uncovered a connection between PA-X and splicing of host RNAs. We have found that PA-X preferentially degrades spliced RNAs in infected cells and, through proximity-dependent protein labeling, we have identified candidate interaction partners of PA-X, which are cellular proteins involved in RNA splicing and 3' end processing. These data have led us to the central hypothesis of this project: PA-X selectively targets RNAs through interactions with cellular splicing and RNA processing machinery. The connection between splicing and PA-X activity is novel among host shutoff RNases. It also suggests that through interactions with splicing factors, PA-X may differentially regulate host RNAs with important functions in immune and inflammatory responses, including spliced vs. intronless types of interferons, key antiviral cytokines. Our objective is to examine the connection between PA-X and cellular mRNA splicing and its effects on cytokine regulation. The long-term goal of our research is to link the molecular function of PA-X to its role in vivo. In Aim 1, we will determine how the number of splice sites and their position affects PA-X's ability to target RNAs, and how widely applicable this is to PA-X variants from divergent influenza strains. We will use a combination of reporter assays and high-throughout RNAseq. In Aim 2, we will define the role of candidate cellular co-factors of PA-X in RNA targeting by PA-X, particularly association with target RNAs and subcellular localization of PA-X using knock-down approaches. We will then use viral mutants to test the role of these interactions in mouse infections. We expect that these experiments will define RNA characteristics and proteins that are important for PA-X activity, expanding our understanding of influenza-host interplay and pointing to strategies to alter PA-X activity for immune modulation.
项目摘要。对甲型流感病毒的先天性免疫和炎症反应是导致流感的主要原因。 流感疾病,因为它促进病毒性肺炎和继发性感染,通过肺损伤。作为 因此,最近已经清楚地表明,阻断流感病毒复制不足以治疗 流行性感冒。需要新的策略来阻断先天免疫和炎症反应, 开发这些策略可以利用病毒蛋白在调节宿主反应中的作用, 包括宿主关闭因子PA-X,其靶向宿主RNA进行降解。PA-X抑制免疫 缺乏PA-X的病毒在小鼠和鸡感染中引发更强的细胞因子反应 模型然而,这些较强的反应并不能促进清除,但在许多情况下, 发病率和死亡率。这表明PA-X具有不同于其他流感免疫的功能 调节剂,并且PA-X可以保护宿主。定义PA-X的作用机制将是 了解PA-X对病毒-宿主相互作用的独特贡献并利用它来调节 宿主对流感的反应。虽然主机关闭因素通常被认为是不加区别的,但我们发现, PA-X是有选择性的,针对特定类型的RNA特别是我们发现了一种联系 PA-X和宿主RNA剪接之间的联系我们已经发现PA-X优先降解剪接的RNA, 感染的细胞,并通过邻近依赖的蛋白质标记,我们已经确定了候选的相互作用 PA-X的配偶体,其是参与RNA剪接和3'末端加工的细胞蛋白。这些数据 这使我们得出了这个项目的中心假设:PA-X通过与细胞相互作用选择性地靶向RNA。 剪接和RNA加工机器。剪接和PA-X活性之间的联系是新的, 主机关闭RNA酶。这也表明,通过与剪接因子的相互作用,PA-X可能在不同的细胞中表达, 调节宿主RNA在免疫和炎症反应中具有重要功能,包括剪接与 无内含子类型的干扰素,关键的抗病毒细胞因子。我们的目标是研究 PA-X与细胞mRNA剪接及其对细胞因子调节的影响我们研究的长期目标是 将PA-X的分子功能与其在体内的作用联系起来。在目标1中,我们将确定剪接位点的数量 它们的位置影响PA-X靶向RNA的能力,以及这对PA-X变体的广泛适用性, 不同的流感病毒株我们将使用报告基因测定和高通量RNAseq的组合。在Aim中 2、明确PA-X的候选细胞辅因子在PA-X靶向RNA中的作用, 与靶RNA的结合和使用敲低方法的PA-X的亚细胞定位。然后我们将 使用病毒突变体来测试这些相互作用在小鼠感染中的作用。我们希望这些实验 将定义对PA-X活性重要的RNA特征和蛋白质,扩展我们的理解 流感-宿主相互作用,并指出改变PA-X活性以调节免疫的策略。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Role of Viral RNA Degrading Factors in Shutoff of Host Gene Expression.
  • DOI:
    10.1146/annurev-virology-100120-012345
  • 发表时间:
    2022-09-29
  • 期刊:
  • 影响因子:
    11.3
  • 作者:
  • 通讯作者:
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Marta Maria Gaglia其他文献

Marta Maria Gaglia的其他文献

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{{ truncateString('Marta Maria Gaglia', 18)}}的其他基金

Determining how Kaposi’s sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses
确定卡波西肉瘤相关疱疹病毒如何劫持半胱天冬酶功能以抑制抗病毒反应
  • 批准号:
    10729751
  • 财政年份:
    2021
  • 资助金额:
    $ 39.42万
  • 项目类别:
Determining how Kaposi's sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses
确定卡波西肉瘤相关疱疹病毒如何劫持半胱天冬酶功能以抑制抗病毒反应
  • 批准号:
    10403006
  • 财政年份:
    2021
  • 资助金额:
    $ 39.42万
  • 项目类别:
Molecular Mechanism of Action of the Influenza PA-X Host Shutoff Protein
流感 PA-X 宿主关闭蛋白的分子机制
  • 批准号:
    9913984
  • 财政年份:
    2018
  • 资助金额:
    $ 39.42万
  • 项目类别:

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