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：
10581061
负责人：
TING-TING WU
金额：
$ 2.58万
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 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10581061
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 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

3&apos 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

展开

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.