Key host factors co-opted to form viral replication organelles

关键宿主因素共同选择形成病毒复制细胞器

• 批准号: 1922895
• 负责人: Peter Nagy
• 金额: $ 56.38万
• 依托单位: University of Kentucky Research Foundation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1922895&HistoricalAwards=false
• 关键词: Key; host; factors; co; opted

Viruses with RNA genomes cause major losses in agriculture and pose significant risks to human health. To multiply in their hosts, these viruses subvert host proteins and cellular membranes to build large viral replication organelles that serve to propagate viruses in the infected cells. These intricate organelles are essential for replication, in part by protecting the viral genomes from attack by the host's immune system. Despite the costly agricultural and medical impact of these viruses, the biogenesis of viral replication organelles is incompletely understood. This project employs plant-infecting tombusviruses to address this key component of the viral life cycle. Insights gained from this project include novel strategies to inhibit the formation of the replication organelles, thereby providing methods to block virus replication and facilitate the development of novel, potent and broad-range antiviral approaches. The research will promote interdisciplinary training for graduate students and a postdoctoral researcher across fields that include plant pathology, biochemistry and cell biology. The lab will also provide hands-on research opportunities for high school students. Tomato bushy stunt virus, which is among the most advanced viral systems, will be used to unravel the roles of host factors in replication organelle formation. The emerging picture with many viruses is that the formation of replication organelles, which concentrate viral and host components and provide protection against antiviral responses by the host, absolutely critical for virus replication. A major breakthrough in this area by the PI is the identification of critical co-opted host proteins, namely Sac1 lipid phosphatase, Fis1 mitochondrial fission protein and Atg11 autophagy scaffold protein as key host factors in the biogenesis of tombusvirus replication organelles. These co-opted cellular proteins interact with each other, with the hijacked cellular membranes and with the viral replication proteins and likely serve as key assembly platforms for the biogenesis of replication organelles. The PI will identify their pro-viral functions based on the awesome power of yeast genetics in combination with elegant cell-free replication assays developed for tombusviruses by the PI. Similar work will be extended to TBSV-plant infections, which will likely lead to major new insights into RNA virus replication and viral pathogenesis. Developing an efficient antiviral strategy based on blocking the function of co-opted Sac1, Fis1 or Atg11 could rapidly be done in the elegant tombusvirus-yeast/plant systems. Inhibition of formation of critical viral replication organelles could be a powerful approach to block virus replication, thus the proposed research will facilitate the development of novel, potent and broad-range antiviral approaches.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

带有RNA基因组的病毒在农业中造成重大损失，并对人类健康构成重大风险。为了在宿主中繁殖，这些病毒破坏宿主蛋白质和细胞膜，以构建大型病毒复制细胞器，这些细胞器用于在受感染细胞中繁殖病毒。这些复杂的细胞器对于复制是必不可少的，部分是通过保护病毒基因组免受宿主免疫系统的攻击。尽管这些病毒对农业和医疗造成了昂贵的影响，但病毒复制细胞器的生物起源还不完全清楚。该项目利用感染植物的tombusviruses来解决病毒生命周期的这一关键组成部分。从该项目中获得的见解包括抑制复制细胞器形成的新策略，从而提供阻断病毒复制的方法，并促进开发新的，有效的和广泛的抗病毒方法。这项研究将促进跨学科培训的研究生和博士后研究人员跨领域，包括植物病理学，生物化学和细胞生物学。该实验室还将为高中生提供动手研究的机会。番茄丛矮病毒是最先进的病毒系统之一，它将被用来阐明宿主因子在复制细胞器形成中的作用。许多病毒的新情况是复制细胞器的形成，它浓缩了病毒和宿主成分，并提供了对宿主抗病毒反应的保护，这对病毒复制绝对至关重要。PI在这一领域的一个重大突破是鉴定了关键的增选宿主蛋白，即Sac 1脂质磷酸酶，Fis 1线粒体分裂蛋白和Atg 11自噬支架蛋白，作为番茄丛矮病毒复制细胞器生物发生中的关键宿主因子。这些增选的细胞蛋白相互作用，与劫持的细胞膜和病毒复制蛋白，并可能作为复制细胞器的生物合成的关键组装平台。PI将根据酵母遗传学的强大功能，结合PI为tombusviruses开发的优雅的无细胞复制试验，鉴定它们的前病毒功能。类似的工作将扩展到TBSV-植物感染，这将可能导致对RNA病毒复制和病毒发病机制的重大新见解。基于阻断增选的Sac 1、Fis 1或Atg 11的功能，开发有效的抗病毒策略可以在优雅的烟草花叶病毒-酵母/植物系统中快速完成。抑制关键病毒复制细胞器的形成可能是阻止病毒复制的有力方法，因此拟议的研究将促进新的，有效的和广泛的抗病毒方法的发展。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

项目成果

Race against Time between the Virus and Host: Actin-Assisted Rapid Biogenesis of Replication Organelles is Used by TBSV to Limit the Recruitment of Cellular Restriction Factors

• DOI: 10.1128/jvi.00168-21
• 发表时间: 2022-05-31
• 期刊: JOURNAL OF VIROLOGY
• 影响因子: 5.4
• 作者: Molho，Melissa;Zhu，Shifeng;Nagy，Peter D.
• 通讯作者: Nagy，Peter D.

Targeting conserved co-opted host factors to block virus replication: Using allosteric inhibitors of the cytosolic Hsp70s to interfere with tomato bushy stunt virus replication

• DOI: 10.1016/j.virol.2021.08.002
• 发表时间: 2021-08-13
• 期刊: VIROLOGY
• 影响因子: 3.7
• 作者: Molho，Melissa;Prasanth，K. Reddisiva;Nagy，Peter D.
• 通讯作者: Nagy，Peter D.

Tombusviruses Target a Major Crossroad in the Endocytic and Recycling Pathways via Co-opting Rab7 Small GTPase

• DOI: 10.1128/jvi.01076-21
• 发表时间: 2021-11-01
• 期刊: JOURNAL OF VIROLOGY
• 影响因子: 5.4
• 作者: Feng, Zhike;Inaba, Jun-ichi;Nagy, Peter D.
• 通讯作者: Nagy, Peter D.