UBIQUITIN AND CELLULAR FACTORS IN CORONAVIRUS ASSEMBLY

冠状病毒组装中的泛素和细胞因子

基本信息

批准号：
7846495
负责人：
Thomas Miller Gallagher
金额：
$ 3.18万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846495
关键词：
Acute Address Animals Antineoplastic Agents Applications Grants Biological Birds Bortezomib Cell membrane Cell secretion Cell surface Cells Complex Containment Coronaviridae Coronavirus Coronavirus Infections Cytoplasmic Tail Defect Disease Domestic Animals E protein Environment Event Exhibits Experimental Designs FDA approved Family Future Gastrointestinal Diseases Hepatitis Human Infection Intervention Life Lung diseases Lysine MG132 Mediating Modeling Modification Molecular Genetics Morphogenesis Mus Organelles Process Proteasome Inhibitor Proteins RNA Viruses Recombinants Research Route Severe Acute Respiratory Syndrome Staging Symptoms Therapeutic Intervention Ubiquitin Ubiquitination Vesicle Viral Viral Proteins Virion Virus Virus Assembly base clinically significant cofactor human coronavirus inhibitor/antagonist member novel particle programs prototype research study respiratory trafficking ubiquitin ligase

项目摘要

Coronaviruses cause respiratory and gastrointestinal diseases in birds and animals. These RNA viruses are genetically variable and can rapidly evolve to infect humans, sometimes causing severe acute respiratory disease. The coronaviruses are set apart in their assembly and secretion from cells by a strategy involving intracellular virus formation and perhaps novel trafficking routes to the outside environment. Further understanding of these late infection events will identify strategies for therapeutic intervention. We have discovered that a prototype mouse hepatitis coronavirus is inhibited at the assembly and / or secretion stages by very low nontoxic concentrations of a proteasome inhibitor. We hypothesize that the inhibitory mechanism involves ubiquitin depletion from cells, a known effect of proteasome inhibitors, because we discovered that the viral E proteins that are central to virus secretion are ubiquitinated on two lysine residues. Our aims are to determine whether pathogenic human coronaviruses are similarly hypersensitive to proteasome inhibitors and then address whether the ubiquitin conjugation of E proteins is central to coronavirus morphogenesis or expulsion out of cells. Our experiments will specifically evaluate whether the locus of inhibitor and ubiquitin action are at the virus secretion stages and will address the novel hypothesis that ubiquitin modifications direct the trafficking of virus-filled organelles to cell surfaces where the virus cargo is liberated. Our findings will reveal novel cell biological features of vesicle formation and organelle transport and will also inform us about the potential to thwart coronaviruses at late infection stages.

冠状病毒引起鸟类和动物的呼吸道和胃肠道疾病。这些 RNA病毒在遗传上是可变的，可以迅速发展以感染人类，有时引起严重的急性呼吸系统疾病。冠状病毒在他们的通过涉及细胞内病毒形成的策略从细胞组装和分泌也许是向外部环境的新型贩运路线。进一步的理解在这些晚期感染事件中，将确定治疗干预的策略。我们已经发现，组装中抑制了小鼠肝炎冠状病毒和 /或分泌阶段，蛋白酶体抑制剂的无毒浓度非常低。我们假设抑制机制涉及细胞中的泛素消耗，a 蛋白酶体抑制剂的已知作用，因为我们发现病毒E蛋白对病毒分泌的核心是在两个赖氨酸残基上泛素化。我们的目标是确定致病性人冠状病毒是否相似蛋白酶体抑制剂，然后解决E蛋白的泛素结合是否是冠状病毒形态发生或从细胞中排出的中心。我们的实验会明确评估抑制剂和泛素作用的基因座是否在病毒上分泌阶段，并将解决泛素修饰直接的新假设将病毒的细胞器贩运到释放病毒货物的细胞表面。我们的发现将揭示囊泡形成和细胞器的新细胞生物学特征运输，还将告知我们迟到的冠状病毒的潜力感染阶段。