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Mechanisms of KSHV posttranscriptional gene regulation

KSHV转录后基因调控机制

基本信息

批准号：
10602409
负责人：
NICHOLAS K CONRAD
金额：
$ 49.2万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10602409
关键词：
Binding Binding Proteins Biochemical Cells Complex Data Ensure Funding Gene Expression Gene Expression Regulation Genes Goals Herpesviridae Human Human Herpesvirus 8 Immunocompromised Host Infection Integration Host Factors Kaposi Sarcoma Late Gene Transcriptions Learning Link Lymphoproliferative Disorders Lytic Phase Masks Mediating Messenger RNA Modeling Molecular Molecular Biology Nuclear Nuclear Decay Nuclear RNA Oncogenic Viruses Pathway interactions Phase Phosphodiesterase I Play Post-Transcriptional Regulation Proteins Quality Control RNA RNA Binding RNA Decay RNA Stability RNA-Binding Proteins Regulation Reporting Resistance Role Testing Transcript Transcriptional Regulation Viral Viral Gene Expression Regulation Viral Genes Virus Work candidate identification exosome helicase human pathogen mRNA Decay mRNA Export mRNA capping novel pathogenic virus premature protein complex recruit tool transcriptome transcriptomics viral RNA

项目摘要

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic virus that causes Kaposi’s sarcoma and lymphoproliferative diseases primarily in immunocompromised patients. Like all herpesviruses, KSHV uses the host gene expression machinery to carefully control the timing and abundance of viral mRNAs in its latent and lytic phases. While emphasis has been placed on transcriptional control, recent reports suggest two distinct interactions between KSHV and host RNA quality control (QC) pathways that degrade nuclear transcripts. The goal of this proposal is to define the molecular mechanisms at the interface of host nuclear RNA QC pathways and KSHV gene expression. The aims will define mechanisms that KSHV uses to protect from or exploit host RNA decay pathways. In addition, some of the host pathways remain poorly understood, so the viral mechanisms will be harnessed to uncover fundamental aspects of human molecular biology. In one pathway studied here, the host RNA QC machinery targets viral transcripts for nuclear decay. To protect its RNAs, the KSHV ORF57 protein counters that pathway likely through other host factors including an RNA-binding protein called ALYREF. In Aims 1 and 2 of the current proposal, the mechanisms of ORF57-mediated protection and the RNAs targeted by specific host factors will be determined in molecular detail. Interestingly, ALYREF and other ORF57 binding proteins are host mRNA export factors. In Aim 3, their proposed roles in viral RNA stability will be tested on host RNAs to determine whether they reflect a general activity of these proteins. In addition to protection from decay, KSHV has been reported to exploit the PABPN1-PAPα/γ mediated RNA decay (PPD) pathway to control temporal expression of late genes. Aim 4 of the current proposal seeks to define the mechanisms of PPD- mediated regulation of viral gene expression and to better define the components of the PPD pathway. Taken together, the proposed KSHV studies investigate the molecular mechanisms involved in nuclear RNA QC pathways to better understand the basic gene expression mechanisms of the human pathogen KSHV and its human host cell.

卡波西肉瘤相关疱疹病毒（KSHV）是一种致癌病毒，主要在免疫功能低下的患者中引起卡波西肉瘤和淋巴组织增生性疾病。像所有疱疹病毒一样，KSHV使用宿主基因表达机制来仔细控制潜伏期和裂解期病毒mRNA的时间和丰度。虽然重点放在转录控制，最近的报告表明，KSHV和宿主RNA质量控制（QC）途径，降解核转录本之间的两个不同的相互作用。本提案的目标是确定宿主核RNA QC途径和KSHV基因表达界面的分子机制。这些目标将定义KSHV用于保护或利用宿主RNA衰变途径的机制。此外，一些宿主途径仍然知之甚少，因此病毒机制将被利用来揭示人类分子生物学的基本方面。在这里研究的一个途径中，宿主RNA QC机制靶向病毒转录物进行核衰变。为了保护它的RNA，KSHV ORF 57蛋白可能通过其他宿主因子（包括一种称为BREF的RNA结合蛋白）来对抗这种途径。在当前提案的目标1和2中，将在分子细节上确定ORF 57介导的保护机制和特定宿主因子靶向的RNA。有趣的是，BMPREF和其他ORF 57结合蛋白是宿主mRNA输出因子。在目标3中，将在宿主RNA上测试它们在病毒RNA稳定性中的拟议作用，以确定它们是否反映这些蛋白质的一般活性。除了保护免于衰变之外，已报道KSHV利用PABPN 1-PAPα/γ介导的RNA衰变（PPD）途径来控制晚期基因的时间表达。本提案的目的4旨在确定PPD介导的病毒基因表达调控机制，并更好地确定PPD途径的组分。总之，拟议的KSHV研究调查了核RNA QC途径中涉及的分子机制，以更好地了解人类病原体KSHV及其人类宿主细胞的基本基因表达机制。