Escape from gammaherpesvirus-induced mRNA destruction

逃避伽马疱疹病毒诱导的 mRNA 破坏

• 批准号: 8676731
• 负责人: Britt A Glaunsinger
• 金额: $ 30.08万
• 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/8676731
• 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; 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; deep sequencing; enhancing factor; gammaherpesvirus; genome-wide; human disease; insight; lytic replication; neoplastic cell; novel; paracrine; poly U polymerase; primary effusion lymphoma; protein complex; tumor microenvironment; 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.

描述（由申请人提供）：伽玛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癌症的主要原因。就KSHV而言，撒哈拉以南非洲的感染率可接近80%，因此，那里的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。这些大的双链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的潜伏状态持续存在。虽然肿瘤发生主要与病毒的潜伏形式相关，但KSHV潜伏通常不是转化事件，KSHV诱导的疾病也需要低水平、持续的裂解复制。裂解复制是必要的，既是新病毒感染原始细胞的来源，也是驱动病毒和宿主旁分泌因子的产生，从而促进潜伏感染细胞的生长并创造适当的肿瘤微环境。然而，在裂解γ疱疹病毒感染期间发生的一个突出表型是细胞信使RNA （mRNA）的广泛破坏，这可能会抑制宿主基因的表达。因此，在裂解性感染细胞诱导特异性宿主基因的必要性和伴随的细胞基因表达阻滞之间存在矛盾。该项目的目标是确定特定宿主基因如何逃避破坏的机制。在溶解性感染期间，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，执行基因表达的关闭。有趣的是，我们已经观察到选择的信息，如白细胞介素-6 （IL-6）对sox诱导的周转是直接难抗的。在IL-6的情况下，我们已经将一个顺式作用的逃逸元件映射到其3'非翻译区域的一个区域，并鉴定了几种与该RNA元件复合物的宿主蛋白。因此，该项目的一个方面是探索这些rna -蛋白质相互作用的机制后果，并确定它们在存在和不存在SOX的情况下如何影响IL-6 mRNA的稳定性。鉴于IL-6在人类疾病中的众多作用，这一信息将与kshv诱导的肿瘤以及该细胞因子在其他癌症中的潜在失调有关。然后，我们将扩大我们的重点，利用从微阵列和深度测序分析中获得的全基因组数据集，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，以及这些途径的操纵如何有助于感染性和遗传性疾病。