Divergent roles of nonsense-mediated RNA decay in oncovirus latency and reactivation

无义介导的RNA衰变在肿瘤病毒潜伏和重新激活中的不同作用

• 批准号: 10880993
• 负责人: Christina M O'Grady
• 金额: $ 12.5万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10880993
• 关键词: B-Lymphocytes; Cell Proliferation; Cells; Complex; Epstein-Barr Virus-Related Lymphoma; Gene Expression; Human; Human Herpesvirus 4; Immune system; Infection; Link; Literature; Lymphoma; Lymphoma cell; Lytic; Lytic Phase; Malignant Neoplasms; Mediating; Mutate; Nasopharynx Carcinoma; Neoplasm Metastasis; Oncogenes; Oncology; Oncornaviruses; Pathway interactions; Phase; Play; Population; Process; Production; Quality Control; RNA; RNA Decay; RNA Splicing; Reporting; Role; Sorting; Stomach Carcinoma; System; Testing; Time; Transcript; Translations; Tumor Suppressor Genes; Tumor Suppressor Proteins; Viral; Viral Genes; Viral Proteins; Virion; Virus; Virus Latency; Yin; cancer cell; cell growth; human pathogen; lytic replication; mutant; novel; pathogen; prevent; reactivation from latency; tumorigenesis; viral RNA

Nonsense-mediated RNA Decay (NMD) is a highly conserved cellular quality control pathway that degrades many mutant or aberrantly spliced RNA transcripts. Reports in the literature have recently linked NMD processes to oncogenesis and metastasis, in complex and sometimes contradictory ways. Often considered a tumor suppressor pathway, NMD is frequently downregulated in cancers, resulting in higher expression of (sometimes mutated) oncogenes. On the other hand, some cancers appear to harness or even enhance the NMD system to degrade transcripts of tumor suppressor genes, dysregulating oncogene expression and leading to increased cancer cell proliferation. EBV is a ubiquitous human pathogen that infects more than 90% of the world’s population and is associated with cancers including lymphomas, gastric carcinoma and nasopharyngeal carcinoma. Typically, EBV persists in host B cells in a latent phase, during which time limited viral gene expression shields the virus from the host immune system. Periodically, reactivation of the lytic cycle leads to viral takeover of the host cell and production of new infectious virions, facilitating viral spread. Interestingly, some EBV RNA transcripts expressed during reactivation appear to be NMD targets. Our preliminary studies have revealed that EBV actively inhibits host cellular NMD during lytic reactivation, presumably preventing degradation of viral RNA transcripts and facilitating viral protein translation and virion production. In contrast, we find that the NMD pathway is active during the latency phase where it likely promotes cell proliferation while simultaneously preventing lytic reactivation. These two opposite modes of engagement form a sort of “yin and yang” relationship between EBV and host NMD that plays a key role in governing its biphasic infection strategy. With this project we will investigate this novel dynamic viral interface with a host system to determine the mechanistic underpinnings of EBV-NMD interactions and determine its functional impact on viral reactivation, viral latency and lymphoma cell growth and proliferation.

无义介导的RNA降解（NMD）是一种高度保守的细胞质量控制途径，其降解许多突变或异常剪接的RNA转录物。文献中的报告最近将NMD过程与肿瘤发生和转移以复杂且有时矛盾的方式联系起来。NMD通常被认为是一种肿瘤抑制途径，在癌症中经常下调，导致癌基因的表达更高（有时突变）。另一方面，一些癌症似乎利用或甚至增强NMD系统来降解肿瘤抑制基因的转录物，使癌基因表达失调并导致癌细胞增殖增加。 EBV是一种普遍存在的人类病原体，感染了世界上90%以上的人口，并与包括淋巴瘤、胃癌和鼻咽癌在内的癌症有关。典型地，EBV在潜伏期持续存在于宿主B细胞中，在此期间，时间有限的病毒基因表达保护病毒免受宿主免疫系统的侵害。周期性地，裂解周期的再活化导致病毒接管宿主细胞并产生新的感染性病毒体，促进病毒传播。有趣的是，在再活化过程中表达的一些EBV RNA转录物似乎是NMD靶标。我们的初步研究表明，EBV在裂解再活化过程中积极抑制宿主细胞NMD，可能阻止病毒RNA转录物的降解并促进病毒蛋白质翻译和病毒体产生。相反，我们发现NMD通路在潜伏期是活跃的，在潜伏期它可能促进细胞增殖，同时防止裂解再激活。这两种相反的接触模式形成了EBV与宿主NMD之间的一种“阴阳”关系，在控制其双相感染策略中起着关键作用。 通过这个项目，我们将研究这种新的动态病毒界面与宿主系统，以确定EBV-NMD相互作用的机制基础，并确定其对病毒再激活，病毒潜伏期和淋巴瘤细胞生长和增殖的功能影响。