How infectious SARS-CoV-2 exploits two ER membrane proteins to promote infection

传染性 SARS-CoV-2 如何利用两种内质网膜蛋白促进感染

• 批准号: 10623348
• 负责人: Billy Tsai
• 金额: $ 38.18万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-17 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623348
• 关键词: 2019-nCoV; Antiviral Agents; Biology; COVID-19; COVID-19 pandemic; Cells; Complex; Cytosol; Data; Development; Disease Progression; Drug Modulation; Endoplasmic Reticulum; Endosomes; FDA approved; Genetic Transcription; Genome; Golgi Apparatus; Impairment; Infection; Integration Host Factors; Life Cycle Stages; Link; Membrane; Membrane Fusion; Membrane Proteins; Methods; Molecular; Nature; Nonstructural Protein; Organelles; Pathway interactions; Process; Protein S; Proteins; RNA; Role; SARS-CoV-2 infection; Shapes; Site; Structural Protein; Structure; Testing; Translating; Translations; Vesicle; Viral; Viral Genome; Viral Proteins; Viral Structural Proteins; Virus; Virus Assembly; Virus Diseases; Virus Replication; endosome membrane; experimental study; genomic RNA; insight; loss of function; multiple myeloma M Protein; particle; polypeptide; receptor mediated endocytosis; recruit; viral genomics

Abstract SARS-CoV-2 exploits the function of the endoplasmic reticulum (ER) to promote its infection life cycle. Despite its strong reliance on the ER, the molecular basis by which SARS-CoV-2 hijacks ER factors to promote defined steps of this life cycle remains unclear. Using infectious SARS-CoV-2, we recently identified two ER membrane proteins – RTN3 and SigmaR1 – as critical host factors that support virus infection. Our findings further reveal that RTN3 plays a role in viral replication, while SigmaR1 exerts a function in viral secretion. However, how SARS-CoV-2 exploits the activities of RTN3 and SigmaR1 to accomplish these two distinct tasks, in mechanistic terms, is completely unknown. Accordingly, the objective of this application is to elucidate the molecular basis by which these two ER membrane factors promote replication and secretion of SARS- CoV-2. We believe these insights will not only illuminate the basic infection mechanism of SARS-CoV-2, but given the continuing global COVID-19 pandemic, may lead to the development of effective anti-virals to blunt the devastating impact of SARS-CoV-2.

摘要 SARS-CoV-2利用内质网（ER）的功能，促进其免疫应答。 感染生命周期尽管它强烈依赖于ER，但其分子基础 SARS-CoV-2劫持ER因子以促进该生命周期的定义步骤仍然存在 不清楚利用传染性SARS-CoV-2，我们最近鉴定了两种ER膜， RTN 3和SigmaR 1蛋白是支持病毒感染的关键宿主因子。我们 研究结果进一步揭示，RTN 3在病毒复制中发挥作用，而SigmaR 1发挥作用， 在病毒分泌中起作用。然而，SARS-CoV-2如何利用RTN 3的活动， 和SigmaR 1来完成这两个不同的任务，在机械方面， 未知因此，本申请的目的是阐明 这两种内质网膜因子促进SARS病毒复制和分泌的机制， 二型冠状病毒我们相信这些见解不仅会阐明基本的感染机制， 但考虑到全球COVID-19大流行的持续， 开发有效的抗病毒药物，以减轻SARS-CoV-2的破坏性影响。