Regulation of mRNA export during gammaherpesvirus infection

伽玛疱疹病毒感染期间 mRNA 输出的调节

• 批准号: 10337074
• 负责人: TING-TING WU
• 金额: $ 37.83万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337074
• 关键词: 3' Untranslated Regions; Acquired Immunodeficiency Syndrome; Affect; Biological; Biology; Cell Nucleus; Cell physiology; Cells; Complement; Complex; Cytoplasm; Development; Disease; Fractionation; Gene Expression; Genes; Genetic Transcription; Goals; Growth; HIV; HIV-1; Herpesviridae; Herpesviridae Infections; Highly Active Antiretroviral Therapy; Homologous Gene; Human; Human Herpesvirus 8; In Vitro; Incidence; Individual; Infection; Kaposi Sarcoma; Knowledge; Label; Life Cycle Stages; Malignant Neoplasms; Mediating; Messenger RNA; Metabolic; Molecular; Mus; Nuclear; Nuclear Export; Open Reading Frames; Oral cavity; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Persons; Production; Proteins; Proteome; Proteomics; RNA; RNA Binding; RNA-Binding Proteins; Regulation; Resources; Rodent; Role; Saliva; Testing; Therapeutic; Transcript; Viral; Virion; Virus; Virus Diseases; Virus Replication; cancer type; cell growth regulation; experimental study; gammaherpesvirus; in vivo; in vivo Model; insight; mRNA Export; mutant; new therapeutic target; novel; novel therapeutic intervention; protein function; response; tool; transcriptome; transcriptomics; virus host interaction

PROJECT SUMMARY Kaposi sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), belongs to the gamma subfamily of human herpesviruses and is responsible for several human malignancies developed in individuals infected with human immunodeficiency virus-1 (HIV-1) or AIDS patients. While the incidence of KSHV diseases has significantly declined since the introduction of highly active antiretroviral therapy (HARRT), Kaposi Sarcoma (KS) remains to be the major type of cancer worldwide in people living with HIV and AIDS. KSHV is primarily transmitted through saliva in endemic regions and frequently results in the development of KS in the oral cavity of AIDS patients. Like all viruses, the ability of KSHV to manipulate host gene expression is vital for its survival. Recently we discovered a novel post-transcriptional mechanism encoded by KSHV to accomplish this. KSHV open reading frame 10 (ORF10) inhibits nuclear export of cellular mRNAs without affecting its own transcripts. This export inhibitory function of ORF10 requires the interaction with an RNA export factor, Rae1. Furthermore, we showed that export inhibition of ORF10 is selective for a subset of mRNAs, and that the 3' untranslated regions of the targeted genes confer transcript sensitivity to ORF10-mediated export inhibition. ORF10 of a closely related rodent virus, murine gammaherpesvirus 68 (MHV-68), also interacts with Rae1 and is responsible for inhibiting nuclear export of mRNA during MHV-68 infection. The conservation of protein interaction and protein function not only underscores the importance of regulating RNA export during gammaherpesvirus infection, but also argues for MHV-68 as an in vivo model to study ORF10. In this proposal, we will elucidate the molecular mechanisms of ORF10-mediated selective RNA export inhibition. The result may reveal a novel cellular regulation of mRNA export. Furthermore, we will determine the functional significance of ORF10 mRNA export inhibition during gammaherpesvirus infection. We will employ the KSHV and MHV-68 ORF10 mutants to identify ORF10-specific changes on host gene expression in the context of infection. Finally, we will define the in vivo role of ORF10 with mouse infection of the MHV-68 ORF10 mutant. These experiments will increase our understanding of how gammaherpesviruses hijack cellular mRNA export pathway to facilitate their own replication. Moreover, the study may uncover cellular functions critical for KSHV replication and provide insights into new therapeutic strategies for KSHV-associated diseases.

项目摘要 Kaposi肉瘤相关的疱疹病毒（KSHV）或人类疱疹病毒-8（HHV-8）属于伽马 人类疱疹病毒的亚家族，并负责个体中发生的几种人类恶性肿瘤 感染人类免疫缺陷病毒-1（HIV-1）或AIDS患者。而KSHV疾病的发生率 自引入高度活性抗逆转录病毒疗法（HARRT），KAPOSI肉瘤以来，已经大大下降了 （KS）在艾滋病毒和艾滋病患者中，在全球范围内仍然是主要的癌症类型。 KSHV主要是 通过唾液在地方性地区传播，经常导致口腔中KS的发展 艾滋病患者。 像所有病毒一样，KSHV操纵宿主基因表达的能力对于其存活至关重要。最近我们 发现了一种由KSHV编码的新颖的转录后机制来实现这一目标。 KSHV开放阅读 框架10（ORF10）抑制细胞mRNA的核出口，而不会影响其自己的转录本。此出口 ORF10的抑制功能需要与RNA输出因子RAE1相互作用。此外，我们表明 ORF10的出口抑制是对mRNA的一部分的选择性，并且3'未翻译区域 靶向基因赋予转录物对ORF10介导的输出抑制的敏感性。密切相关的ORF10 啮齿动物病毒，鼠γ鞘膜病毒68（MHV-68）也与RAE1相互作用，并负责抑制 MHV-68感染期间mRNA的核出口。蛋白质相互作用和蛋白质功能的保护 不仅强调了调节在伽马梅病毒感染期间RNA导出的重要性，而且还强调 主张MHV-68作为研究ORF10的体内模型。在此提案中，我们将阐明分子 ORF10介导的选择性RNA输出抑制的机理。结果可能显示出新的细胞 mRNA导出的调节。此外，我们将确定ORF10 mRNA导出的功能意义 γ掌病毒感染期间的抑制作用。我们将使用KSHV和MHV-68 ORF10突变体识别 ORF10特异性在感染背景下对宿主基因表达的变化。最后，我们将定义体内 ORF10在MHV-68 ORF10突变体的小鼠感染中的作用。 这些实验将增加我们对伽马病毒如何劫持细胞mRNA导出的理解 促进自己复制的途径。此外，该研究可能会发现对KSHV至关重要的细胞功能 复制并提供有关KSHV相关疾病的新治疗策略的见解。