Mechanisms of Gene Regulation by EBV EBNA-1 Protein

EBV EBNA-1蛋白的基因调控机制

• 批准号: 7681398
• 负责人: JEFFERY T SAMPLE
• 金额: $ 37.92万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681398
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Apoptotic; B-Lymphocytes; Binding Sites; Biology; Cell division; Cells; Class; Cytotoxic T-Lymphocytes; Data; Development; Disease; Down-Regulation; EBNA-1 protein; EBV-associated disease; EBV-associated malignancy; EBV-encoded nuclear antigen 1; Ensure; Episome; Epitopes; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Equilibrium; Event; Exons; Foundations; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genome; Growth; Herpesviridae; Heterogeneous Nuclear RNA; Homeostasis; Human; Human Herpesvirus 4; Immune; Immune system; Immunologic Surveillance; Individual; Infection; Infectious Mononucleosis; Intervention; Knowledge; Life; Lymphoma; Lytic Phase; MHC Class I Genes; Maintenance; Mediating; Medical Surveillance; Messenger RNA; Oncogenic; Pathogenesis; Peptides; Play; Process; Property; Proteins; RNA Splicing; Relative (related person); Repression; Resistance; Risk; Risk Factors; Role; Secondary to; Simplexvirus; T-Lymphocyte; Thinking; Transcript; Transcription Initiation Site; Viral; Viral Genes; Viral Genome; Viral Proteins; Work; cell killing; defined contribution; gene repression; immune function; infected B cell; insight; latent infection; mRNA Expression; mRNA Precursor; multicatalytic endopeptidase complex; pathogen; prevent; programs; promoter; tumorigenic

hin B lymphocytes with little overt disease. However, a breakdown in immune surveillance, e.g., as a consequence of AIDS, remains a significant risk factor for development of EBV-associated lymphoma, underscoring the highly evolved equilibrium that exists between this potentially oncogenic herpesvirus and the host immune system. This equilibrium is dependent on a selective down-regulation of EBV latency-associated gene expression during establishment of persistent infection that ultimately restricts expression to viral genes critical for maintenance of persistence, while precluding those with acute transforming properties and/or which encode dominant epitopes recognized by the EBV-specific T-cell surveillance. A pivotal process in this transition to restricted latency is a promoter switching event that enables exclusive expression of the essential EBV genome-maintenance protein, EBNA-1, from the promoter Qp, which can be negatively regulated through two EBNA-1 binding sites immediately downstream of its transcription start site. Our recent efforts to define the mechanism of EBNA-1 repression revealed that it acts not by inhibition of transcription, as originally believed, but by suppression of pre-mRNA processing. The principal significance of this autoregulation, furthermore, has recently become apparent. Although EBNA-1 was earlier thought to be ¿invisible¿ to the host immune surveillance as a consequence of its ability to inhibit in cis its degradation by the cell proteasome, thereby preventing presentation of EBNA-1 peptide epitopes in association with HLA class I molecules, subsequent studies indicated that cytotoxic T cells that recognize EBNA-1 not only exist, but that they are directed towards peptides generated during actual synthesis of EBNA-1, not by the degradation of mature EBNA-1. Thus, resistance to proteasomal degradation is secondary to the autoregulated expression of EBNA-1 as the primary mechanism employed by EBV to restrict EBNA-1-specific T-cell killing. Further, recently described antiapoptotic properties of EBNA-1 suggest that it may have tumorigenic potential. We hypothesize, therefore, that the autoregulatory function of EBNA-1 is highly critical to EBV persistence and its associated pathogenic potential: it ensures sufficient EBNA-1 for genome maintenance, while limiting EBNA-1 synthesis below a threshold that, if exceeded, would subject latently infected B cells to elimination by EBNA-1-specific cytotoxic T cells, and potentially oncogenic transformation. We propose three specific aims to help us reach our long-term objective of defining the contribution of EBNA-1 autoregulation to EBV biology, immune evasion and pathogenesis: 1) Define the mechanism of EBNA-1 autoregulation; 2) Elucidate the contributions of EBNA-1 autoregulation to the growth and restricted programs of latency; and 3) Define the respective roles of Qp and Fp, an alternative adjacent EBNA-1 promoter, in EBV infection.

Hin B淋巴细胞几乎没有明显的疾病。但是，免疫监视的细分，例如 艾滋病的后果仍然是发展与EBV相关淋巴瘤发展的重要危险因素， 强调了这种潜在的致癌疱疹病毒和 主机免疫系统。该等效因素取决于与EBV延迟相关的选择性下调 建立持续感染期间的基因表达，最终将表达限制为病毒基因 对维持持久性至关重要，同时排除那些具有急性转化特性和/或的人 编码EBV特异性T细胞监视所识别的主要表位。这是一个关键过程 过渡到限制延迟是一个启动子切换事件，可独家表达必需品 启动子QP的EBV基因组维护蛋白EBNA-1，可以通过负调节 两个EBNA-1结合位点其转录起始位点的下游。我们最近为定义的努力 EBNA-1表达的机制表明，它不是通过抑制转录的作用，正如最初认为的那样， 但是通过抑制前MRNA处理。此外，这种自动调节的主要意义具有 最近变得显而易见。虽然EBNA-1早些时候被认为是对宿主免疫的看不见的 监视由于其能够抑制CIS降解的能力，因此 防止与HLA I类分子相关的EBNA-1-1肽表位，随后 研究表明，识别EBNA-1的细胞毒性T细胞不仅存在，而且针对 在EBNA-1的实际合成过程中产生的肽，而不是由于成熟的EBNA-1的降解。那， 对蛋白酶体降解的抗性是eBNA-1自动调节表达的继发性 EBV进行的机制限制了EBNA-1特异性T细胞杀戮。此外，最近描述了抗凋亡 EBNA-1的性质表明它可能具有致瘤潜力。因此，我们假设 EBNA-1的自调功能对EBV持久性及其相关的致病性至关重要 潜力：它确保了足够的EBNA-1用于基因组维持，同时将EBNA-1合成限制在A以下 阈值，如果超过该阈值，则会通过EBNA-1特异性细胞毒性T消除潜在感染的B细胞 细胞，并可能进行致癌转化。我们提出了三个特定的目标，以帮助我们实现长期 定义EBNA-1自动调节对EBV生物学，免疫进化和 发病机理：1）定义EBNA-1自动调节的机制； 2）阐明EBNA-1的贡献 对延迟的增长和限制计划进行自动调节； 3）定义QP和 FP是EBV感染中的另一种相邻的EBNA-1启动子。