Escape from gammaherpesvirus-induced mRNA destruction

逃避伽马疱疹病毒诱导的 mRNA 破坏

• 批准号: 8148069
• 负责人: Britt A Glaunsinger
• 金额: $ 30.55万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8148069
• 关键词: 3' Untranslated Regions; Adult; Affect; Africa South of the Sahara; Cancer Etiology; Cells; Communicable Diseases; Data Set; Disease; Double Stranded DNA Virus; Elements; Event; Gene Expression; Gene Expression Regulation; Genes; Goals; Growth; Growth Factor; Hereditary Disease; Herpesviridae Infections; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immunocompromised Host; Incidence; Individual; Infection; Integration Host Factors; Interleukin-6; Kaposi Sarcoma; Lymphocyte; Lymphoma; Lytic; Lytic Phase; Malignant Neoplasms; Maps; Mediating; Messenger RNA; Multicentric Angiofollicular Lymphoid Hyperplasia; Neoplasms; Pathogenesis; Pathway interactions; Phenotype; Play; Population; Production; Proteins; RNA; RNA Degradation; RNA Stability; RNA-Protein Interaction; Refractory; Role; Sequence Analysis; Source; Viral; Virus; Virus Diseases; base; cytokine; effusion; enhancing factor; gammaherpesvirus; genome-wide; human disease; insight; lytic replication; neoplastic cell; novel; paracrine; poly U polymerase; protein complex; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The gammaherpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are major causes of cancers in immunocompromised individuals. In the case of KSHV, infection rates in sub-Saharan Africa can approach 80% and, as a result, the incidence there of Kaposi's sarcoma is rising and it is emerging as one of the most common adult malignancies. These large double stranded DNA viruses are amplified during lytic replication, but persist for the lifetime of their host in a nonreplicative, latent state. While tumorigenesis is predominantly associated with the latent form of the virus, for KSHV latency is generally not a transforming event and KSHV-induced diseases also require low-level, ongoing lytic replication. Lytic replication is necessary both as a source of new virus to infect naive cells, and to drive production of viral and host paracrine factors that enhance growth of latently infected cells and create an appropriate tumor microenvironment. However, one prominent phenotype occurring during lytic gammaherpesvirus infection is the widespread destruction of cellular messenger RNA (mRNA), which potently inhibits host gene expression. Thus, there is a paradox between the necessity for lytically infected cells to induce specific host genes and the concomitant block in cellular gene expression. The goal of this project is to determine mechanistically how specific host genes evade destruction. Degradation of mRNA during lytic infection is orchestrated by the viral SOX protein, which coordinates with cellular RNA turnover factors to execute shutoff of gene expression. Interestingly, we have observed that select messages such as interleukin-6 (IL-6) are directly refractory to SOX-induced turnover. In the case of IL-6, we have mapped a cis-acting escape element to a region of its 3' untranslated region, and identified several host proteins that complex with this RNA element. One aspect of the project is therefore to explore the mechanistic consequences of these RNA-protein interactions, and determine how they influence IL-6 mRNA stability in the presence and absence of SOX. Given the numerous roles for IL-6 in human disease, this information will be relevant both to KSHV-induced neoplasms as well as potential dysregulation of this cytokine in other cancers. We will then broaden our focus to explore potentially conserved mechanisms of escape, using genome-wide data sets obtained from microarray and deep sequencing analyses. We anticipate these studies may reveal novel pathways that control message fate, and how manipulation of such pathways contributes to both infectious and genetic diseases. PUBLIC HEALTH RELEVANCE: Human gammaherpesviruses are a major cause of cancers in immunocompromised individuals. In order to cause disease, these viruses drive their infected cells to produce proteins that assist in the growth and survival of neighboring tumor cells. This project aims to determine how these necessary host factors accumulate, even though the majority of other host genes are eliminated by these viruses.

描述（由申请人提供）：伽马疱疹病毒卡波西肉瘤相关疱疹病毒（KSHV）和EB病毒（EBV）是免疫功能低下个体患癌症的主要原因。就 KSHV 而言，撒哈拉以南非洲地区的感染率可接近 80%，因此卡波西肉瘤的发病率正在上升，并正在成为最常见的成人恶性肿瘤之一。这些大型双链 DNA 病毒在裂解复制过程中被扩增，但在宿主的一生中以非复制、潜伏状态持续存在。虽然肿瘤发生主要与病毒的潜伏形式有关，但对于 KSHV 潜伏期通常不是转化事件，KSHV 诱导的疾病也需要低水平、持续的裂解复制。裂解复制对于感染幼稚细胞的新病毒来源以及驱动病毒和宿主旁分泌因子的产生是必要的，这些旁分泌因子可增强潜伏感染细胞的生长并创造适当的肿瘤微环境。然而，裂解性伽马疱疹病毒感染期间出现的一种显着表型是细胞信使 RNA (mRNA) 的广泛破坏，从而有效抑制宿主基因表达。因此，裂解感染细胞诱导特定宿主基因的必要性与随之而来的细胞基因表达的阻断之间存在矛盾。该项目的目标是从机制上确定特定宿主基因如何逃避破坏。裂解感染期间 mRNA 的降解是由病毒 SOX 蛋白精心策划的，该蛋白与细胞 RNA 周转因子协调以执行基因表达的关闭。有趣的是，我们观察到白细胞介素 6 (IL-6) 等特定信息对 SOX 诱导的更新具有直接抵抗力。就 IL-6 而言，我们将顺式作用逃逸元件定位到其 3' 非翻译区的一个区域，并鉴定了几种与该 RNA 元件复合的宿主蛋白。因此，该项目的一方面是探索这些 RNA-蛋白质相互作用的机制后果，并确定它们如何在存在和不存在 SOX 的情况下影响 IL-6 mRNA 的稳定性。鉴于 IL-6 在人类疾病中的多种作用，这一信息将与 KSHV 诱导的肿瘤以及其他癌症中该细胞因子的潜在失调相关。然后，我们将利用从微阵列和深度测序分析中获得的全基因组数据集，扩大关注范围，探索潜在的保守逃逸机制。我们预计这些研究可能会揭示控制信息命运的新途径，以及操纵这些途径如何导致传染病和遗传性疾病。 公共卫生相关性：人类伽玛疱疹病毒是免疫功能低下个体患癌症的主要原因。为了引起疾病，这些病毒驱使受感染的细胞产生有助于邻近肿瘤细胞生长和存活的蛋白质。该项目旨在确定这些必要的宿主因子如何积累，即使大多数其他宿主基因被这些病毒消除。