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Regulation of mRNA export during gammaherpesvirus infection

伽玛疱疹病毒感染期间 mRNA 输出的调节

基本信息

批准号：
10581524
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581524
关键词：
3&apos Untranslated Regions Acquired Immunodeficiency Syndrome Affect Biological Biology Cell Nucleus Cell physiology Cells Complement Complex Cytoplasm Development Disease Fractionation Gene Expression Genes Goals Growth HIV-1 HIV/AIDS 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 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 posttranscriptional protein function response tool transcriptome transcriptomics transmission process virus host interaction

项目摘要

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.

项目摘要卡波西肉瘤相关疱疹病毒（KSHV）或人疱疹病毒-8（HHV-8），属于γ-疱疹病毒人类疱疹病毒的一个亚科，并导致在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）或艾滋病患者。虽然KSHV疾病的发病率自从引入高效抗逆转录病毒治疗（HARRT）以来，卡波西肉瘤的发病率显著下降， (KS)它仍然是全球艾滋病毒和艾滋病感染者的主要癌症类型。KSHV主要是在流行地区通过唾液传播，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其生存至关重要。最近我们发现了一种由KSHV编码的新的转录后机制来实现这一点。KSHV开路阅读框架10（ORF 10）抑制细胞mRNA的核输出而不影响其自身的转录物。此导出 ORF 10的抑制功能需要与RNA输出因子Rae 1相互作用。此外，我们还展示了 ORF 10的输出抑制对mRNA的一个子集是选择性的，并且ORF 10的3'非翻译区是选择性的。靶向基因赋予转录物对ORF 10介导的输出抑制的敏感性。ORF 10的一个密切相关的啮齿动物病毒，鼠γ疱疹病毒68（MHV-68），也与Rae 1相互作用，并负责抑制在MHV-68感染期间mRNA的核输出。蛋白质相互作用和蛋白质功能的保守性不仅强调了在γ疱疹病毒感染期间调节RNA输出的重要性，主张MHV-68作为研究ORF 10的体内模型。在这个建议中，我们将阐明分子 ORF 10介导的选择性RNA输出抑制机制。结果可能揭示了一种新的细胞 mRNA输出的调控。此外，我们将确定ORF 10 mRNA输出的功能意义，在γ疱疹病毒感染期间抑制。我们将使用KSHV和MHV-68 ORF 10突变体来鉴定感染背景下宿主基因表达的ORF 10特异性变化。最后，我们将定义体内 ORF 10在小鼠感染MHV-68 ORF 10突变体中的作用。这些实验将增加我们对γ疱疹病毒如何劫持细胞mRNA输出的了解以促进自身的复制。此外，该研究可能揭示KSHV的关键细胞功能，复制，并为KSHV相关疾病的新治疗策略提供见解。