Mechanisms of reversible DUB oxidation in genome stability pathways - Revision

项目摘要/摘要 目前的新冠肺炎大流行(冠状病毒病-2019年)，这是一种呼吸道疾病，已经 自疫情爆发以来，已在100多个国家和地区造成500多万例确诊病例和350,000多人死亡 2019年末出现的SARS-CoV-2是由一种新型病毒株SARS-CoV-2引起的，它是一种包膜的阳性- 冠状病毒科的正义单链RNAβ冠状病毒。我的实验室有一个很长的- 了解环境产生的细胞复制如何受到监管的长期兴趣 小分子，包括ROS、有毒重金属、化学污染物和致癌物。类似 对于人类来说，病毒副本，如冠状病毒Plpro，是裂解泛素的蛋白酶 或来自原蛋白或来自目标蛋白上的结合物的泛素样蛋白。在这样做的过程中，病毒 DUBS劫持了受感染细胞中泛素化动力学的平衡，潜在地扰乱了 多种细胞功能，包括细胞周期调节、蛋白酶体和溶酶体蛋白 降解、基因表达、激酶激活、DNA修复，最终有利于微生物 发病机制。病毒复制如何特别容易受到环境暴露的影响，例如 ROS和化学污染物还没有被充分开发，特别是作为新的调节剂 人类的致病机制。因为它与SARS-CoV-2在全球的快速传播和 新冠肺炎在美国和世界范围内的流行，我们将把我们的重点放在 研究目标1)SARS-CoV-2 PlPro蛋白酶活性(裂解 原蛋白、泛素和ISG15结合蛋白)可以由环境- 产生的小分子，以及2)识别与新冠肺炎疾病相关的细胞靶点 PLPro对人肺上皮细胞病毒感染的影响。

PROJECT SUMMARY/ABSTRACT The current pandemic of COVID-19 (Coronavirus Disease-2019), a respiratory disease that has led to over 5 million confirmed cases and over 350,000 fatalities in over 100 countries since its emergence in late 2019, is caused by a novel virus strain, SARS-CoV-2, an enveloped, positive- sense, single-stranded RNA beta-coronavirus of the family Coronaviridae. My lab has a long- standing interest in understanding how cellular DUBs are regulated by environmentally-produced small molecules, including ROS, toxic heavy metals, chemical pollutants and carcinogens. Similar to human DUBs, viral DUBs, such as the coronavirus Plpro, are proteases that cleave ubiquitin or ubiquitin-like proteins from pro-proteins or from conjugates on target proteins. In doing so, viral DUBs hijack the balance of ubiquitination dynamics in infected cells, potentially disrupting numerous cellular functions, including cell cycle regulation, proteasomal and lysosomal protein degradation, gene expression, kinase activation, DNA repair and ultimately favoring microbial pathogenesis. How viral DUBs are particularly susceptible to environmental exposures, such as ROS and chemical pollutants, have not been adequately explored, especially as novel modulators of human pathogenesis. As it pertains to the rapid global spread of SARS-CoV-2 and the prevalence of COVID-19 disease in the U.S. population and worldwide, we will be focusing our research goals on understanding 1) how the SARS-CoV-2 Plpro protease activity (cleavage of pro-proteins, ubiquitin-, and ISG15-conjugated proteins) can be regulated by environmentally- generated small molecules, and 2) identifying COVID-19 disease-relevant cellular targets of the Plpro upon viral infection in human lung epithelial cells.