Mechanisms of KSHV post-transcriptional gene regulation

KSHV转录后基因调控机制

• 批准号: 8278289
• 负责人: NICHOLAS K CONRAD
• 金额: $ 4.77万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278289
• 关键词: Affect; Area; Binding; Biogenesis; Biology; Cell Nucleus; Cells; Complex; Environment; Event; Gene Expression; Gene Expression Regulation; Generations; Genes; Goals; Herpesviridae; Human; Human Herpesvirus 8; Indium; Introns; Kaposi Sarcoma; Knowledge; Lead; Life; Life Cycle Stages; Ligands; Link; Lymphoma; Lymphoproliferative Disorders; Lytic; Lytic Phase; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular; Multicentric Angiofollicular Lymphoid Hyperplasia; Nuclear; Nuclear RNA; Pathway interactions; Process; Production; Proteins; Publishing; Quality Control; RNA; RNA Binding; RNA Decay; RNA Recognition Motif; RNA Stability; Reporting; Research; Role; System; Testing; Transcript; Viral; Viral Genes; Viral Proteins; Virion; Virus; Work; cell growth regulation; design; effusion; in vivo; insight; novel; novel therapeutic intervention; pathogen; programs; public health relevance; research study; tumorigenesis; viral RNA; virus host interaction

DESCRIPTION (provided by applicant): Viruses use a wide spectrum of molecular mechanisms to favor their own gene expression in the complex environment of an infected host cell. Recent advances suggest that viral regulation of cellular RNA decay pathways is more common than previously appreciated. For example, several factors in the Kaposi's sarcoma-associated herpesvirus (KSHV) have been demonstrated to regulate host or viral RNA turnover rates. In this proposal, a role for the KSHV ORF57 protein in viral transcript stability is examined. ORF57 is a lytic phase protein that is essential for viral replication and has been reported to affect a wide variety of nuclear events in mRNA biogenesis, but its molecular mechanisms remain unknown. The experiments in this proposal are designed to test the hypothesis that ORF57 binds to nuclear RNAs and protects them from cellular RNA decay pathways. Specifically, the studies described here will elucidate the molecular mechanisms of ORF57 nuclear function by examining 1) the effects of ORF57 on nuclear stability of viral mRNAs, 2) the relationship between RNA binding and ORF57 function, and 3) the roles of ORF57 RNA-binding and stability activities in the context of viral lytic infection. Understanding the molecular mechanism of ORF57 is fundamental to understanding the biology of KSHV, the causative agent for Kaposi's sarcoma, primary effusion lymphoma (PEL), and some types of multicentric Castleman's disease (MCD). An appreciation of ORF57 molecular mechanisms may lead to novel therapeutic approaches and bolster knowledge of the pathways important for controlling tumorigenesis. Thus, by revealing the mechanisms of ORF57 function, these studies will provide molecular insights into this important human pathogen and into the biology of its human host cells. PUBLIC HEALTH RELEVANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) causes several malignancies including Kaposi's sarcoma and certain lymphoproliferative disorders. This proposal examines specific mechanisms of KSHV gene regulation essential for viral replication. A deeper understanding of KSHV gene regulation will lead to a more complete knowledge of this important human pathogen and may reveal aspects of gene regulation in its human host cell.

描述(由申请人提供)：病毒使用广泛的分子机制在受感染的宿主细胞的复杂环境中有利于自己的基因表达。最近的进展表明，病毒对细胞RNA衰退途径的调控比之前所认识的更常见。例如，卡波西肉瘤相关疱疹病毒(KSHV)中的几个因子已被证明调节宿主或病毒的RNA周转率。在这项建议中，研究了KSHV ORF57蛋白在病毒转录稳定性中的作用。ORF57是病毒复制所必需的裂解期蛋白，已被报道在mRNA生物发生过程中影响多种核事件，但其分子机制尚不清楚。这项提议中的实验旨在测试ORF57与核RNA结合并保护它们免受细胞RNA衰变途径的假设。具体地说，这些研究将通过检测1)ORF57对病毒mRNAs核稳定性的影响，2)RNA结合与ORF57功能的关系，以及3)ORF57 RNA结合和稳定活性在病毒裂解感染中的作用来阐明ORF57核功能的分子机制。了解ORF57的分子机制是了解KSHV生物学的基础，KSHV是Kaposi肉瘤、原发渗出性淋巴瘤(PEL)和某些类型的多中心Castleman病(MCD)的病原体。对ORF57分子机制的认识可能会导致新的治疗方法，并加强对控制肿瘤发生的重要途径的了解。因此，通过揭示ORF57的功能机制，这些研究将为这种重要的人类病原体及其人类宿主细胞的生物学提供分子洞察力。 公共卫生相关性：Kaposi肉瘤相关疱疹病毒(KSHV)可导致多种恶性肿瘤，包括Kaposi肉瘤和某些淋巴增生性疾病。这项建议研究了KSHV基因调控对病毒复制至关重要的特定机制。对KSHV基因调控的深入了解将使人们对这种重要的人类病原体有更全面的了解，并可能揭示其在人类宿主细胞中的基因调控方面。